Novel compounds for the treatment of neurodegenerative diseases

ABSTRACT

This invention provides novel compounds and the novel compounds for use as a medicine, more in particular for the prevention or treatment of neurodegenerative disorders, more specifically certain neurological disorders, such as disorders collectively known as tauopathies, and disorders characterised by cytotoxic α-synuclein amyloidogenesis. The present invention also relates to the use of said novel compounds for the manufacture of medicaments useful for treating such neurodegenerative disorders. The present invention further relates to pharmaceutical compositions including said novel compounds and to methods for the preparation of said novel compounds. The compounds have the formula (A1), wherein R 1 , R 2 , R 4 , R 5 , R 6 , E, n, Y 1 , Y 2 , Y 3 , Y 4 , Y 5 , B, R 8 , and m are as defined in the claims.

FIELD OF THE INVENTION

The present invention relates to novel compounds and to the novelcompounds for use as a medicine, more in particular for the preventionor treatment of neurodegenerative disorders, more specifically certainneurological disorders, such as disorders collectively known astauopathies, and disorders characterised by cytotoxic α-synucleinamyloidogenesis. The present invention also relates to the compounds foruse as a medicaments and to the use of said compounds for themanufacture of medicaments useful for treating such neurodegenerativedisorders. The present invention further relates to pharmaceuticalcompositions including said novel compounds and to methods for thepreparation of said novel compounds.

BACKGROUND OF THE INVENTION

TAU is an intracellular protein with the ability to bind andconsequently stabilise and define microtubule structure and function.Apart from this physiological function TAU also plays a direct role innumerous neurodegenerative disorders collectively known as “tauopathies”with the most notable examples being Alzheimer's disease, Pick'sdisease, corticobasal degeneration, progressive supranuclear palsy,frontotemporal dementia and parkinsonism linked to chromosome 17(FTDP-17).

Tauopathies are characterised by insoluble aggregates or polymers of tauwhich are formed by self-polymerisation of tau monomers. The precisemolecular mechanisms involved in TAU aggregation is not clearly knownbut may involve partial denaturation or misfolding of the TAU protein inconformations with a high propensity to self-organise into higher orderstructures. An important aspect of the TAU aggregation is its inherentcytotoxicity, which reduces cellular integrity or even triggers celldeath. In case of neurodegenerative diseases, loss of affected neuronsleads to cognitive and/or motor dysfunctioning. A direct role of TAU indisease onset has been established unequivocally by the elucidation offamilial mutations in TAU which appear to be responsible for a veryearly and sometimes aggressive form of tauopathy. Such mutationscomprise changes in the amino acid sequence of TAU that promote toxicaggregation and thereby provoke loss of cellular integrity.

Treatments aimed to suppress cytotoxic TAU pathology are presently notavailable. Currently used treatments for Alzheimer's disease offer asmall symptomatic benefit, but no treatments to delay or halt theprogression of the disease are available.

α-Synuclein is a neuronal protein which originally has been associatedwith neuronal plasticity during Zebra finch song learning. Although itsrole at the molecular level is at present largely elusive it appears tohave lipid bi-layer (or membrane) with binding properties important forpreserving proper transport of neurotransmitter vesicles to the axonalends of neurons presumably to ensure proper signalling at the synapse.Apart from its physiological role in brain cells, human α-synuclein alsopossesses pathological features that underlie a plethora ofneurodegenerative diseases including Parkinson's disease, diffuse Lewybody disease, traumatic brain injury, amyotrophic lateral sclerosis,Niemann-Pick disease, Hallervorden-Spatz syndrome, Down syndrome,neuroaxonal dystrophy, multiple system atrophy and Alzheimer's disease.These neurological disorders are characterised by the presence ofinsoluble α-synuclein polymers or aggregates usually residing withinneuronal cells, although in the case of Alzheimer's disease α-synuclein(or proteolytic fragments thereof) constitutes the non-amyloid componentof extracellular “amyloid-β plaques”. It is widely believed that theamyloidogenic properties α-synuclein disrupt cellular integrity leadingto dysfunctioning or death of affected neurons resulting in cognitiveand/or motoric decline as it is found in patients suffering from suchdiseases. The aggregation of α-synuclein is at present very poorlydefined, but constitutes most likely a multi-step process whereinself-polymerization of α-synuclein into insoluble aggregates is precededby the formation of soluble protofibrils of α-synuclein monomers.Self-association may be triggered by the formation of alternativeconformations of α-synuclein monomers with high propensity topolymerize. Several studies using neuronal cell lines or whole animalshave shown that formation of reactive oxygen species (hereinafterabbreviated as ROS) appear to stimulate noxious α-synucleinamyloidogenesis. For instance paraquat (an agent stimulating ROSformation within the cell) has been recognized as a stimulator ofα-synuclein aggregation. Like in animals, exposure to paraquat isbelieved to induce the formation of synuclein inclusions, andconsequently neurodegeneration, especially of dopaminergic neurons inhumans. Dopaminergic neurons appear to be particularly sensitive becausethe concurrent dopamine metabolism may on the one hand contributesignificantly to the oxidative stress load but may on the other handresult in kinetic stabilisation of highly toxic protofibrillarα-synuclein species by dopamine (or its metabolic derivatives).Parkinson's disease is characterised by a selective loss of dopaminergicsubstantia nigra cells and therefore treatment of animals (or neuronalcells) with paraquat is a common well-accepted experimental set-up forstudying synucleopathies, in particular Parkinson's disease.

Apart from ROS, mutations in the coding region of the α-synuclein genehave also been identified as stimulators of self-polymerizationresulting in early disease onset as it is observed in families afflictedby such mutations. Finally, increased expression of α-synuclein alsopromotes early disease onset as evidenced by a duplication ortriplication of the α-synuclein gene in the genome of some individuals.The molecular mechanism by which α-synuclein self-association triggerscellular degeneration is at present largely unknown. Although it hasbeen speculated that insoluble aggregates affect cellular integrity, ithas recently been suggested that soluble protofibrillar intermediates ofthe aggregation process are particularly toxic for the cell as opposedto mature insoluble fibrils which may be inert end-products or may evenserve as cytoprotective reservoirs of otherwise harmful soluble species.Therapeutic attempts to inhibit formation of insoluble aggregates maytherefore be conceptually wrong, possibly even promoting diseaseprogress.

While the identification of pathological α-synuclein mutationsunequivocally revealed a causative factor of a plethora ofneurodegenerative disorders, treatments ensuring suppression of toxicα-synuclein amyloidogenesis are presently not available. Onlysymptomatic treatments of Parkinson's disease exist. These treatmentsaim e.g. at increasing dopamine levels in order to replenish its loweredlevel due to degeneration of dopaminergic neurons, for instance byadministrating L-DOPA or inhibitors of dopamine breakdown. Although suchtreatments suppress disease symptoms to some extent, they are onlytemporarily effective and certainly do not slow down ongoing neuronaldegeneration.

Thus there is a stringent need for new drugs for therapeutic and/orpreventive applications that target the underlying molecular mechanismof TAU and/or α-synuclein related pathologies such as Alzheimer'sdisease in order to reduce neuronal cell death and/or degeneration, orat least retard the onset of the most disabilitating manifestationsthereof. Therefore a goal of the present invention is to satisfy thisurgent need by identifying efficient pharmaceutically active ingredientsthat are active against TAU and/or α-synuclein related pathologies suchas Alzheimer's disease, less toxic and/or more stable (i.e. chemicallystable, metabolically stable) and that can be useful, either alone or incombination with other active ingredients, for the treatment of TAUand/or α-synuclein related pathologies such as Alzheimer's disease inanimals and more specifically in humans.

It is also known to the skilled in the art that the physicochemicalproperties of known drugs as well as their ADME-Tox (administration,distribution, metabolism, excretion) properties may limit or prohibittheir use in the treatment of diseases. Therefore, a problem of existingdrugs that can be overcome with the compounds of the invention can beselected from poor or inadequate physicochemical or ADME-Tox propertiessuch as toxicity, solubility, LogP, CYP inhibition, hepatic stability,plasmatic stability, among others.

SUMMARY OF THE INVENTION

The present invention is based on the unexpected finding that at leastone of the above-mentioned problems can be solved by a novel class ofcompounds. The present invention provides compounds which are useful forpreventing or treating neurodegenerative disorders, especiallytauopathies. The present invention demonstrates that these compoundsefficiently inhibit the tau-aggregation induced toxicity which isresponsible for neurodegeneration. Therefore, these novel compoundsconstitute a useful class of compounds that can be used in the treatmentand/or prevention of neurodegenerative disorders in animals, morespecifically in humans.

A first aspect of the present invention therefore provides compoundsaccording to formula (AA1),

wherein,

-   -   E is independently selected from CR³; and N;    -   each R¹, R³, R⁴ and R⁶ is independently selected from hydrogen;        halogen; —OH; —OR¹⁰; —SH; —SR¹⁰; —S(O)R¹¹; —S(O)₂R¹¹;        —SO₂NR¹²R¹³; trifluoromethyl; trifluoromethoxy; nitro;        —NHC(O)R¹⁰; —NHS(O)₂R¹⁰; —NHC(O)NR¹²R¹³; —NR¹⁰C(O)R¹⁰;        —NR¹⁰S(O)₂R¹⁰; —NR¹⁰C(O)NR¹²R¹³; —NR¹²R¹³; -cyano; —COOH;        —COOR¹⁰; —C(O)NR¹²R¹³; —C(O)R¹¹; alkyl; alkenyl; alkynyl; aryl;        heterocycle; arylalkylene; arylalkenylene; arylalkynylene;        heterocycle-alkylene; heterocycle-alkenylene; and        heterocycle-alkynylene;        -   and wherein said alkyl, alkenyl, alkynyl, aryl, heterocycle,            arylalkylene, arylalkenylene, arylalkynylene,            heterocycle-alkylene, heterocycle-alkenylene or            heterocycle-alkynylene, optionally includes one or more            heteroatoms in the alkyl(ene), alkenyl(ene) or alkynyl(ene)            moiety, said heteroatoms being selected from the atoms O, S            and N;        -   and wherein said alkyl, alkenyl, alkynyl, aryl, heterocycle,            arylalkylene, arylalkenylene, arylalkynylene,            heterocycle-alkylene, heterocycle-alkenylene or            heterocycle-alkynylene can be unsubstituted or substituted            with one or more Z;        -   and wherein a carbon atom or heteroatom of said alkyl,            alkenyl, alkynyl, aryl, heterocycle, arylalkylene,            arylalkenylene, arylalkynylene, heterocycle-alkylene,            heterocycle-alkenylene or heterocycle-alkynylene, can be            oxidized to form a C═O, C═S, N═O, N═S, S═O or S(O)₂;    -   R² is selected from hydrogen; alkyl; alkenyl; and alkynyl;    -   R⁵ is independently selected from halogen; —OH; —OR¹⁰; —SH;        —SR¹⁰; —S(O)R¹¹; —S(O)₂R¹¹; —SO₂NR¹²R¹³; trifluoromethyl;        trifluoromethoxy; nitro; —NHC(O)R¹⁰; —NHS(O)₂R¹⁰;        —NHC(O)NR¹²R¹³; —NR¹⁰C(O)R¹⁰; —NR¹⁰S(O)₂R¹⁰; —NR¹⁰C(O)NR¹²R¹³;        —NR¹²R¹³; -cyano; —COOH; —COOR¹⁰; —C(O)NR¹²R¹³; —C(O)R¹¹; alkyl;        alkenyl; alkynyl; aryl; heterocycle; arylalkylene;        arylalkenylene; arylalkynylene; heterocycle-alkylene;        heterocycle-alkenylene; and heterocycle-alkynylene;        -   and wherein said alkyl, alkenyl, alkynyl, aryl, heterocycle,            arylalkylene, arylalkenylene, arylalkynylene,            heterocycle-alkylene, heterocycle-alkenylene or            heterocycle-alkynylene, optionally includes one or more            heteroatoms in the alkyl(ene), alkenyl(ene) or alkynyl(ene)            moiety, said heteroatoms being selected from the atoms O, S            and N;        -   and wherein said alkyl, alkenyl, alkynyl, aryl, heterocycle,            arylalkylene, arylalkenylene, arylalkynylene,            heterocycle-alkylene, heterocycle-alkenylene or            heterocycle-alkynylene can be unsubstituted or substituted            with one or more Z;        -   and wherein a carbon atom or heteroatom of said alkyl,            alkenyl, alkynyl, aryl, heterocycle, arylalkylene,            arylalkenylene, arylalkynylene, heterocycle-alkylene,            heterocycle-alkenylene or heterocycle-alkynylene, can be            oxidized to form a C═O, C═S, N═O, N═S, S═O or S(O)₂;    -   n is selected from 0; 1; 2;    -   one of X¹, X², X³, X⁴ and X⁵ is selected from CW; whereby W is

while each of the other of X¹, X², X³, X⁴ and X⁵ is independentlyselected from CZ¹; N; NR¹⁰¹; and CO; wherein maximally three of X¹, X²,X³, X⁴ and X⁵ are independently selected from N; NR¹⁰¹; and CO;preferably one of X¹, X², X³, X⁴ and X⁵ is selected from CW; whereby Wis

while each of the other of X¹, X², X³, X⁴ and X⁵ is independentlyselected from CZ¹; N; and NR¹⁰¹; wherein maximally three of X¹, X², X³,X⁴ and X⁵ are independently selected from N; and NR¹⁰¹;

-   -   B represents a cyclic structure selected from cycloalkyl;        cycloalkenyl; cycloalkynyl; aryl; and heterocycle;    -   m is selected from 0; 1; 2; 3; 4 and 5;    -   R⁸ is independently selected from hydrogen; halogen; alkyl;        alkenyl; alkynyl; —OH; —OR²⁰; —SH; —SR²⁰; —S(O)R²¹; —S(O)₂R²¹;        —SO₂NR²²R²³; trifluoromethyl; trifluoromethoxy; nitro;        —NHC(O)R²⁰; —NHS(O)₂R²⁰; —NHC(O)NR²²R²³; —NR²⁰C(O)R²⁰;        —NR¹⁰S(O)₂R²⁰; —NR²⁰C(O)NR²²R²³; —NR²²R²³; -cyano; —COOH;        —COOR²⁰; —C(O)NR²²R²³; and —C(O)R²¹;        -   and wherein said alkyl, alkenyl and alkynyl optionally            includes one or more heteroatoms, said heteroatoms being            selected from the atoms O, S and N;        -   and wherein said alkyl, alkenyl and alkynyl can be            unsubstituted or substituted with one or more Z²;        -   and wherein a carbon atom or heteroatom of said alkyl,            alkenyl and alkynyl, can be oxidized to form a C—O, C═S,            N═O, N═S, S═O or S(O)₂;    -   each Z is independently selected from halogen; —OH; —OR¹⁰; —SH;        —SR¹⁰; —S(O)R¹¹; —S(O)₂R¹¹; —SO₂NR¹²R¹³; trifluoromethyl;        trifluoromethoxy; nitro; —NHC(O)R¹⁰; —NHS(O)₂R¹⁰;        —NHC(O)NR¹²R¹³; —NR¹⁰C(O)R¹⁰; —NR¹⁰S(O)₂R¹⁰; —NR¹⁰C(O)NR¹²R¹³;        —NR¹²R¹³; -cyano; —COOH; —COOR¹⁰; —C(O)NR¹²R¹³; and —C(O)R¹¹;    -   each Z¹ is independently selected from hydrogen; alkyl; and Z²;    -   each Z² is independently selected from halogen; —OH; —OR²⁰; —SH;        —SR²⁰; —S(O)R²¹; —S(O)₂R²¹; —SO₂NR²²R²³; trifluoromethyl;        trifluoromethoxy; nitro; —NHC(O)R²⁰; —NHS(O)₂R²⁰;        —NHC(O)NR²²R²³; —NR²⁰C(O)R²⁰; —NR²⁰S(O)₂R²⁰; —NR²⁰C(O)NR²²R²³;        —NR²²R²³; -cyano; —COOH; —COOR²⁰; —C(O)NR²²R²³; and —C(O)R²¹;    -   each R¹⁰ is independently selected from alkyl; alkenyl; alkynyl;        aryl; heterocycle; arylalkylene; arylalkenylene; arylalkynylene;        heterocycle-alkylene; heterocycle-alkenylene and        heterocycle-alkynylene;        -   and wherein said alkyl, alkenyl, alkynyl, aryl, heterocycle,            arylalkylene, arylalkenylene, arylalkynylene,            heterocycle-alkylene, heterocycle-alkenylene or            heterocycle-alkynylene optionally include one or more            heteroatoms in the alkyl(ene), alkenyl(ene) or alkynyl(ene)            moiety, said heteroatom selected from O, S and N;        -   and wherein a carbon atom or heteroatom of said alkyl,            alkenyl, alkynyl, aryl, heterocycle, arylalkylene,            arylalkenylene, arylalkynylene, heterocycle-alkylene,            heterocycle-alkenylene or heterocycle-alkynylene, can be            oxidized to form a C═O, C═S, N═O, N═S, S═O or S(O)₂;    -   each R¹⁰¹ is independently selected from hydrogen and R¹⁰;    -   each R¹¹ is independently selected from hydroxyl; alkyl;        alkenyl; alkynyl; aryl; heterocycle; arylalkylene;        arylalkenylene; arylalkynylene; heterocycle-alkylene;        heterocycle-alkenylene and heterocycle-alkynylene;        -   and wherein said alkyl, alkenyl, alkynyl, aryl, heterocycle,            arylalkylene, arylalkenylene, arylalkynylene,            heterocycle-alkylene, heterocycle-alkenylene or            heterocycle-alkynylene optionally include one or more            heteroatoms in the alkyl(ene), alkenyl(ene) or alkynyl(ene)            moiety, said heteroatom selected from O, S and N;        -   and wherein a carbon atom or heteroatom of said alkyl,            alkenyl, alkynyl, aryl, heterocycle, arylalkylene,            arylalkenylene, arylalkynylene, heterocycle-alkylene,            heterocycle-alkenylene or heterocycle-alkynylene, can be            oxidized to form a C═O, C═S, N═O, N═S, S═O or S(O)₂;    -   each R¹² and R¹³ is independently selected from hydrogen; alkyl;        alkenyl; alkynyl; aryl; heterocycle; arylalkylene;        arylalkenylene; arylalkynylene; heterocycle-alkylene;        heterocycle-alkenylene and heterocycle-alkynylene;        -   and wherein said alkyl, alkenyl, alkynyl, aryl, heterocycle,            arylalkylene, arylalkenylene, arylalkynylene,            heterocycle-alkylene, heterocycle-alkenylene or            heterocycle-alkynylene optionally include one or more            heteroatoms in the alkyl(ene), alkenyl(ene) or alkynyl(ene)            moiety, said heteroatom selected from O, S and N;        -   and wherein a carbon atom or heteroatom of said alkyl,            alkenyl, alkynyl, aryl, heterocycle, arylalkylene,            arylalkenylene, arylalkynylene, heterocycle-alkylene,            heterocycle-alkenylene or heterocycle-alkynylene, can be            oxidized to form a C═O, C═S, N═O, N═S, S═O or S(O)₂;        -   and wherein R¹² and R¹³ can be taken together in order to            form a (4-, 5-, 6-, or 7-membered) heterocycle which can be            unsubstituted or substituted;    -   each R²⁰ is independently selected from alkyl; alkenyl; and        alkynyl;        -   and wherein said alkyl, alkenyl, alkynyl optionally include            one or more heteroatoms in the alkyl, alkenyl or alkynyl            moiety, said heteroatom selected from O, S and N;        -   and wherein a carbon atom or heteroatom of said alkyl,            alkenyl, alkynyl can be oxidized to form a C—O, C═S, N═O,            N═S, S═O or S(O)₂;    -   each R²¹ is independently selected from hydroxyl; alkyl;        alkenyl; and alkynyl;        -   and wherein said alkyl, alkenyl or alkynyl optionally            include one or more heteroatoms in the alkyl, alkenyl or            alkynyl moiety, said heteroatom selected from O, S and N;        -   and wherein a carbon atom or heteroatom of said alkyl,            alkenyl or alkynyl can be oxidized to form a C═O, C═S, N═O,            N═S, S═O or S(O)₂;    -   each R²² and R²³ is independently selected from hydrogen; alkyl;        alkenyl; and alkynyl;        -   and wherein said alkyl, alkenyl or alkynyl optionally            include one or more heteroatoms in the alkyl, alkenyl or            alkynyl moiety, said heteroatom selected from O, S and N;        -   and wherein a carbon atom or heteroatom of said alkyl,            alkenyl or alkynyl can be oxidized to form a C═O, C═S, N═O,            N═S, S═O or S(O)₂;        -   and wherein R²² and R²³ can be taken together in order to            form a (4-, 5-, 6-, or 7-membered) non-aromatic heterocycle            which can be unsubstituted or substituted;            and isomers (in particular stereoisomers, enantiomers or            tautomers), solvates, hydrates, salts (in particular            pharmaceutically acceptable salts) or prodrugs thereof.

In analogy, the first aspect of the present invention therefore providescompounds according to formula (A1),

wherein,

-   -   E is independently selected from CR³; and N;    -   each R¹, R³, R⁴ and R⁶ is independently selected from hydrogen;        halogen; —OH; —OR¹⁰; —SH; —SR¹⁰; —S(O)R¹¹; —S(O)₂R¹¹;        —SO₂NR¹²R¹³; trifluoromethyl; trifluoromethoxy; nitro;        —NHC(O)R¹⁰; —NHS(O)₂R¹⁰; —NHC(O)NR¹²R¹³; —NR¹⁰C(O)R¹⁰;        —NR¹⁰S(O)₂R¹⁰; —NR¹⁰C(O)NR¹²R¹³; —NR¹²R¹³; -cyano; —COOH;        —COOR¹⁰; —C(O)NR¹²R¹³; —C(O)R¹¹; alkyl; alkenyl; alkynyl; aryl;        heterocycle; arylalkylene; arylalkenylene; arylalkynylene;        heterocycle-alkylene; heterocycle-alkenylene; and        heterocycle-alkynylene;        -   and wherein said alkyl, alkenyl, alkynyl, aryl, heterocycle,            arylalkylene, arylalkenylene, arylalkynylene,            heterocycle-alkylene, heterocycle-alkenylene or            heterocycle-alkynylene, optionally includes one or more            heteroatoms in the alkyl(ene), alkenyl(ene) or alkynyl(ene)            moiety, said heteroatoms being selected from the atoms O, S            and N;        -   and wherein said alkyl, alkenyl, alkynyl, aryl, heterocycle,            arylalkylene, arylalkenylene, arylalkynylene,            heterocycle-alkylene, heterocycle-alkenylene or            heterocycle-alkynylene can be unsubstituted or substituted            with one or more Z;        -   and wherein a carbon atom or heteroatom of said alkyl,            alkenyl, alkynyl, aryl, heterocycle, arylalkylene,            arylalkenylene, arylalkynylene, heterocycle-alkylene,            heterocycle-alkenylene or heterocycle-alkynylene, can be            oxidized to form a C═O, C═S, N═O, N═S, S═O or S(O)₂;    -   R² is selected from hydrogen; alkyl; alkenyl; and alkynyl;    -   R⁵ is independently selected from halogen; —OH; —OR¹⁰; —SH;        —SR¹⁰; —S(O)R¹¹; —S(O)₂R¹¹; —SO₂NR¹²R¹³; trifluoromethyl;        trifluoromethoxy; nitro; —NHC(O)R¹⁰; —NHS(O)₂R¹⁰;        —NHC(O)NR¹²R¹³; —NR¹⁰C(O)R¹⁰; —NR¹⁰S(O)₂R¹⁰; —NR¹⁰C(O)NR¹²R¹³;        —NR¹²R¹³; -cyano; —COOH; —COOR¹⁰; —C(O)NR¹²R¹³; —C(O)R¹¹; alkyl;        alkenyl; alkynyl; aryl; heterocycle; arylalkylene;        arylalkenylene; arylalkynylene; heterocycle-alkylene;        heterocycle-alkenylene; and heterocycle-alkynylene;        -   and wherein said alkyl, alkenyl, alkynyl, aryl, heterocycle,            arylalkylene, arylalkenylene, arylalkynylene,            heterocycle-alkylene, heterocycle-alkenylene or            heterocycle-alkynylene, optionally includes one or more            heteroatoms in the alkyl(ene), alkenyl(ene) or alkynyl(ene)            moiety, said heteroatoms being selected from the atoms O, S            and N;        -   and wherein said alkyl, alkenyl, alkynyl, aryl, heterocycle,            arylalkylene, arylalkenylene, arylalkynylene,            heterocycle-alkylene, heterocycle-alkenylene or            heterocycle-alkynylene can be unsubstituted or substituted            with one or more Z;        -   and wherein a carbon atom or heteroatom of said alkyl,            alkenyl, alkynyl, aryl, heterocycle, arylalkylene,            arylalkenylene, arylalkynylene, heterocycle-alkylene,            heterocycle-alkenylene or heterocycle-alkynylene, can be            oxidized to form a C═O, C═S, N═O, N═S, S═O or S(O)₂;    -   n is selected from 0; 1; and 2;    -   each of Y¹, Y², Y³, Y⁴ and Y⁵ is independently selected from        CZ¹; N; NR¹⁰¹; and CO; wherein at least two of Y¹, Y², Y³, Y⁴        and Y⁵ are selected from CZ¹; preferably each of Y¹, Y², Y³, Y⁴        and Y⁵ is independently selected from CZ¹; N; and NR¹⁰¹; wherein        at least two of Y¹, Y², Y³, Y⁴ and Y⁵ are selected from CZ¹;    -   B represents a cyclic structure selected from cycloalkyl;        cycloalkenyl; cycloalkynyl; aryl; and heterocycle;    -   m is selected from 0; 1; 2; 3; 4 and 5;    -   each R⁸ is independently selected from hydrogen; halogen; alkyl;        alkenyl; alkynyl; —OH; —OR²⁰; —SH; —SR²⁰; —S(O)R²¹; —S(O)₂R²¹;        —SO₂NR²²R²³; trifluoromethyl; trifluoromethoxy; nitro;        —NHC(O)R²⁰; —NHS(O)₂R²⁰; —NHC(O)NR²²R²³; —NR²⁰C(O)R²⁰;        —NR¹⁰S(O)₂R²⁰; —NR²⁰C(O)NR²²R²³; —NR²²R²³; -cyano; —COOH;        —COOR²⁰; —C(O)NR²²R²³; and —C(O)R²¹;        -   and wherein said alkyl, alkenyl and alkynyl optionally            includes one or more heteroatoms, said heteroatoms being            selected from the atoms O, S and N;        -   and wherein said alkyl, alkenyl and alkynyl can be            unsubstituted or substituted with one or more Z²;        -   and wherein a carbon atom or heteroatom of said alkyl,            alkenyl and alkynyl, can be oxidized to form a C—O, C═S,            N═O, N═S, S═O or S(O)₂;    -   each Z is independently selected from halogen; —OH; —OR¹⁰; —SH;        —SR¹⁰; —S(O)R¹¹; —S(O)₂R¹¹; —SO₂NR¹²R¹³; trifluoromethyl;        trifluoromethoxy; nitro; —NHC(O)R¹⁰; —NHS(O)₂R¹⁰;        —NHC(O)NR¹²R¹³; —NR¹⁰C(O)R¹⁰; —NR¹⁰S(O)₂R¹⁰; —NR¹⁰C(O)NR¹²R¹³;        —NR¹²R¹³; -cyano; —COOH; —COOR¹⁰; —C(O)NR¹²R¹³; and —C(O)R¹¹;    -   each Z¹ is independently selected from hydrogen; alkyl; and Z²;    -   each Z² is independently selected from halogen; —OH; —OR²⁰; —SH;        —SR²⁰; —S(O)R²¹; —S(O)₂R²¹; —SO₂NR²²R²³; trifluoromethyl;        trifluoromethoxy; nitro; —NHC(O)R²⁰; —NHS(O)₂R²⁰;        —NHC(O)NR²²R²³; —NR²⁰C(O)R²⁰; —NR²⁰S(O)₂R²⁰; —NR²⁰C(O)NR²²R²³;        —NR²²R²³; -cyano; —COOH; —COOR²⁰; —C(O)NR²²R²³; and —C(O)R²¹;    -   each R¹⁰ is independently selected from alkyl; alkenyl; alkynyl;        aryl; heterocycle; arylalkylene; arylalkenylene; arylalkynylene;        heterocycle-alkylene; heterocycle-alkenylene and        heterocycle-alkynylene;        -   and wherein said alkyl, alkenyl, alkynyl, aryl, heterocycle,            arylalkylene, arylalkenylene, arylalkynylene,            heterocycle-alkylene, heterocycle-alkenylene or            heterocycle-alkynylene optionally include one or more            heteroatoms in the alkyl(ene), alkenyl(ene) or alkynyl(ene)            moiety, said heteroatom selected from O, S and N;        -   and wherein a carbon atom or heteroatom of said alkyl,            alkenyl, alkynyl, aryl, heterocycle, arylalkylene,            arylalkenylene, arylalkynylene, heterocycle-alkylene,            heterocycle-alkenylene or heterocycle-alkynylene, can be            oxidized to form a C═O, C═S, N═O, N═S, S═O or S(O)₂;    -   each R¹⁰¹ is independently selected from hydrogen and R¹⁰;    -   each R¹¹ is independently selected from hydroxyl; alkyl;        alkenyl; alkynyl; aryl; heterocycle; arylalkylene;        arylalkenylene; arylalkynylene; heterocycle-alkylene;        heterocycle-alkenylene and heterocycle-alkynylene;        -   and wherein said alkyl, alkenyl, alkynyl, aryl, heterocycle,            arylalkylene, arylalkenylene, arylalkynylene,            heterocycle-alkylene, heterocycle-alkenylene or            heterocycle-alkynylene optionally include one or more            heteroatoms in the alkyl(ene), alkenyl(ene) or alkynyl(ene)            moiety, said heteroatom selected from O, S and N;        -   and wherein a carbon atom or heteroatom of said alkyl,            alkenyl, alkynyl, aryl, heterocycle, arylalkylene,            arylalkenylene, arylalkynylene, heterocycle-alkylene,            heterocycle-alkenylene or heterocycle-alkynylene, can be            oxidized to form a C═O, C═S, N═O, N═S, S═O or S(O)₂;    -   each R¹² and R¹³ is independently selected from hydrogen; alkyl;        alkenyl; alkynyl; aryl; heterocycle; arylalkylene;        arylalkenylene; arylalkynylene; heterocycle-alkylene;        heterocycle-alkenylene and heterocycle-alkynylene;        -   and wherein said alkyl, alkenyl, alkynyl, aryl, heterocycle,            arylalkylene, arylalkenylene, arylalkynylene,            heterocycle-alkylene, heterocycle-alkenylene or            heterocycle-alkynylene optionally include one or more            heteroatoms in the alkyl(ene), alkenyl(ene) or alkynyl(ene)            moiety, said heteroatom selected from O, S and N;        -   and wherein a carbon atom or heteroatom of said alkyl,            alkenyl, alkynyl, aryl, heterocycle, arylalkylene,            arylalkenylene, arylalkynylene, heterocycle-alkylene,            heterocycle-alkenylene or heterocycle-alkynylene, can be            oxidized to form a C═O, C═S, N═O, N═S, S═O or S(O)₂;        -   and wherein R¹² and R¹³ can be taken together in order to            form a (4-, 5-, 6-, or 7-membered) heterocycle which can be            unsubstituted or substituted;    -   each R²⁰ is independently selected from alkyl; alkenyl; and        alkynyl;        -   and wherein said alkyl, alkenyl, alkynyl optionally include            one or more heteroatoms in the alkyl, alkenyl or alkynyl            moiety, said heteroatom selected from O, S and N;        -   and wherein a carbon atom or heteroatom of said alkyl,            alkenyl, alkynyl can be oxidized to form a C—O, C═S, N═O,            N═S, S═O or S(O)₂;    -   each R²¹ is independently selected from hydroxyl; alkyl;        alkenyl; and alkynyl;        -   and wherein said alkyl, alkenyl or alkynyl optionally            include one or more heteroatoms in the alkyl, alkenyl or            alkynyl moiety, said heteroatom selected from O, S and N;        -   and wherein a carbon atom or heteroatom of said alkyl,            alkenyl or alkynyl can be oxidized to form a C—O, C═S, N═O,            N═S, S═O or S(O)₂;    -   each R²² and R²³ is independently selected from hydrogen; alkyl;        alkenyl; and alkynyl;        -   and wherein said alkyl, alkenyl or alkynyl optionally            include one or more heteroatoms in the alkyl, alkenyl or            alkynyl moiety, said heteroatom selected from O, S and N;        -   and wherein a carbon atom or heteroatom of said alkyl,            alkenyl or alkynyl can be oxidized to form a C—O, C═S, N═O,            N═S, S═O or S(O)₂;        -   and wherein R²² and R²³ can be taken together in order to            form a (4-, 5-, 6-, or 7-membered) non-aromatic heterocycle            which can be unsubstituted or substituted;            and isomers (in particular stereoisomers, enantiomers or            tautomers), solvates, hydrates, salts (in particular            pharmaceutically acceptable salts) or prodrugs thereof.

According to an embodiment, the present invention provides compounds ofFormula (A1) or (AA1), wherein

-   -   one of X¹, X², X³, X⁴ and X⁵ is selected from CW; whereby W is

while each of the other of X¹, X², X³, X⁴ and X⁵ is independentlyselected from CZ¹; N; and NR¹⁰¹; wherein maximally three of X¹, X², X³,X⁴ and X⁵ are independently selected from N; and NR¹⁰¹;

-   -   E is independently selected from CR³; and N;    -   each R¹, R³, R⁴ and R⁶ is independently selected from hydrogen;        halogen; —OH; —OR¹⁰; —SH; —SR¹⁰; —S(O)R¹¹; —S(O)₂R¹¹;        —SO₂NR¹²R¹³; trifluoromethyl; trifluoromethoxy; nitro;        —NHC(O)R¹⁰; —NHS(O)₂R¹⁰; —NHC(O)NR¹²R¹³; —NR¹⁰C(O)R¹⁰;        —NR¹⁰S(O)₂R¹⁰; —NR¹⁰C(O)NR¹²R¹³; —NR¹²R¹³; -cyano; —COOH;        —COOR¹⁰; —C(O)NR¹²R¹³; —C(O)R¹¹; alkyl; alkenyl; alkynyl; aryl;        heterocycle; arylalkylene; arylalkenylene; arylalkynylene;        heterocycle-alkylene; heterocycle-alkenylene; and        heterocycle-alkynylene;    -   R² is selected from hydrogen; alkyl; alkenyl; and alkynyl;    -   R⁵ is independently selected from halogen; —OH; —OR¹⁰; —SH;        —SR¹⁰; —S(O)R¹¹; —S(O)₂R¹¹; —SO₂NR¹²R¹³; trifluoromethyl;        trifluoromethoxy; nitro; —NHC(O)R¹⁰; —NHS(O)₂R¹⁰;        —NHC(O)NR¹²R¹³; —NR¹⁰C(O)R¹⁰; —NR¹⁰S(O)₂R¹⁰; —NR¹⁰C(O)NR¹²R¹³;        —NR¹²R¹³; -cyano; —COOH; —COOR¹⁰; —C(O)NR¹²R¹³; —C(O)R¹¹; alkyl;        alkenyl; alkynyl; aryl; heterocycle; arylalkylene;        arylalkenylene; arylalkynylene; heterocycle-alkylene;        heterocycle-alkenylene; and heterocycle-alkynylene;    -   n is selected from 0; 1; and 2;    -   each of Y¹, Y², Y³, Y⁴ and Y⁵ is independently selected from        CZ¹; N; NR¹⁰¹; and CO; wherein at least two of Y¹, Y², Y³, Y⁴        and Y⁵ are selected from CZ¹;    -   B represents a cyclic structure selected from cycloalkyl;        cycloalkenyl; cycloalkynyl; aryl; and heterocycle;    -   m is selected from 0; 1; 2; 3; 4 and 5;    -   each R⁸ is independently selected from hydrogen; halogen; alkyl;        alkenyl; alkynyl; —OH; —OR²⁰; —SH; —SR²⁰; —S(O)R²¹; —S(O)₂R²¹;        —SO₂NR²²R²³; trifluoromethyl; trifluoromethoxy; nitro;        —NHC(O)R²⁰; —NHS(O)₂R²⁰; —NHC(O)NR²²R²³; —NR²⁰C(O)R²⁰;        —NR¹⁰S(O)₂R²⁰; —NR²⁰C(O)NR²²R²³; —NR²²R²³; -cyano; —COOH;        —COOR²⁰; —C(O)NR²²R²³; and —C(O)R²¹;    -   each Z is independently selected from halogen; —OH; —OR¹⁰; —SH;        —SR¹⁰; —S(O)R¹¹; —S(O)₂R¹¹; —SO₂NR¹²R¹³; trifluoromethyl;        trifluoromethoxy; nitro; —NHC(O)R¹⁰; —NHS(O)₂R¹⁰;        —NHC(O)NR¹²R¹³; —NR¹⁰C(O)R¹⁰; —NR¹⁰S(O)₂R¹⁰; —NR¹⁰C(O)NR¹²R¹³;        —NR¹²R¹³; -cyano; —COOH; —COOR¹⁰; —C(O)NR¹²R¹³; and —C(O)R¹¹;    -   each Z¹ is independently selected from hydrogen; alkyl; and Z²;    -   each Z² is independently selected from halogen; —OH; —OR²⁶; —SH;        —SR²⁰; —S(O)R²¹; —S(O)₂R²¹; —SO₂NR²²R²³; trifluoromethyl;        trifluoromethoxy; nitro; —NHC(O)R²⁰; —NHS(O)₂R²⁰;        —NHC(O)NR²²R²³; —NR²⁰C(O)R²⁰; —NR²⁰S(O)₂R²⁰; —NR²⁰C(O)NR²²R²³;        —NR²²R²³; -cyano; —COOH; —COOR²⁰; —C(O)NR²²R²³; and —C(O)R²¹;    -   each R¹⁰ is independently selected from alkyl; alkenyl; alkynyl;        aryl; heterocycle; arylalkylene; arylalkenylene; arylalkynylene;        heterocycle-alkylene; heterocycle-alkenylene and        heterocycle-alkynylene;    -   each R¹⁰¹ is independently selected from hydrogen and R¹⁰;    -   each R¹¹ is independently selected from hydroxyl; alkyl;        alkenyl; alkynyl; aryl; heterocycle; arylalkylene;        arylalkenylene; arylalkynylene; heterocycle-alkylene;        heterocycle-alkenylene and heterocycle-alkynylene;    -   each R¹² and R¹³ is independently selected from hydrogen; alkyl;        alkenyl; alkynyl; aryl; heterocycle; arylalkylene;        arylalkenylene; arylalkynylene; heterocycle-alkylene;        heterocycle-alkenylene and heterocycle-alkynylene;        -   and wherein R¹² and R¹³ can be taken together in order to            form a (4-, 5-, 6-, or 7-membered) heterocycle which can be            unsubstituted or substituted;    -   each R²⁰ is independently selected from alkyl; alkenyl; and        alkynyl;    -   each R²¹ is independently selected from hydroxyl; alkyl;        alkenyl; and alkynyl;    -   each R²² and R²³ is independently selected from hydrogen; alkyl;        alkenyl; and alkynyl;        -   and wherein R²² and R²³ can be taken together in order to            form a (4-, 5-, 6-, or 7-membered) non-aromatic heterocycle            which can be unsubstituted or substituted.

According to an embodiment, the present invention provides compounds ofFormula (A1) or (AA1), wherein

-   -   one of X¹, X², X³, X⁴ and X⁵ is selected from CW; whereby W is

while each of the other of X¹, X², X³, X⁴ and X⁵ is independentlyselected from CZ¹; N; and NR¹⁰¹; wherein maximally three of X¹, X², X³,X⁴ and X⁵ are independently selected from N; and NR¹⁰¹;

-   -   E is independently selected from CR³; and N;    -   each R¹, R³, R⁴ and R⁶ is independently selected from hydrogen;        halogen; —OH; —OR¹⁰; —SH; —SR¹⁰; —S(O)R¹¹; —S(O)₂R¹¹;        —SO₂NR¹²R¹³; trifluoromethyl; trifluoromethoxy; nitro;        —NHC(O)R¹⁰; —NHS(O)₂R¹⁰; —NHC(O)NR¹²R¹³; —NR¹⁰C(O)R¹⁰;        —NR¹⁰S(O)₂R¹⁰; —NR¹⁰C(O)NR¹²R¹³; —NR¹²R¹³; -cyano; —COOH;        —COOR¹⁰; —C(O)NR¹²R¹³; —C(O)R¹¹; alkyl; alkenyl; alkynyl; aryl;        heterocycle; arylalkylene; arylalkenylene; arylalkynylene;        heterocycle-alkylene; heterocycle-alkenylene; and        heterocycle-alkynylene;    -   R² is selected from hydrogen; alkyl; alkenyl; and alkynyl;    -   R⁵ is independently selected from halogen; —OH; —OR¹⁰; —SH;        —SR¹⁰; —S(O)R¹¹; —S(O)₂R¹¹; —SO₂NR¹²R¹³; trifluoromethyl;        trifluoromethoxy; nitro; —NHC(O)R¹⁰; —NHS(O)₂R¹⁰;        —NHC(O)NR¹²R¹³; —NR¹⁰C(O)R¹⁰; —NR¹⁰S(O)₂R¹⁰; —NR¹⁰C(O)NR¹²R¹³;        —NR¹²R¹³; -cyano; —COOH; —COOR¹⁰; —C(O)NR¹²R¹³; —C(O)R¹¹; alkyl;        alkenyl; alkynyl; aryl; heterocycle; arylalkylene;        arylalkenylene; arylalkynylene; heterocycle-alkylene;        heterocycle-alkenylene; and heterocycle-alkynylene;    -   n is selected from 0; 1; and 2;    -   each of Y¹, Y², Y³, Y⁴ and Y⁵ is independently selected from        CZ¹; N; NR¹⁰¹; and CO; wherein at least two of Y¹, Y², Y³, Y⁴        and Y⁵ are selected from CZ¹;    -   B represents a cyclic structure selected from cycloalkyl;        cycloalkenyl; cycloalkynyl; aryl; and heterocycle;    -   m is selected from 0; 1; 2; 3; 4 and 5;    -   each R⁸ is independently selected from hydrogen; halogen; alkyl;        alkenyl; alkynyl; —OH; —OR²⁰; —SH; —SR²⁰; —S(O)R²¹; —S(O)₂R²¹;        —SO₂NR²²R²³; trifluoromethyl; trifluoromethoxy; nitro;        —NHC(O)R²⁰; —NHS(O)₂R²⁰; —NHC(O)NR²²R²³; —NR²⁰C(O)R²⁰;        —NR¹⁰S(O)₂R²⁰; —NR²⁰C(O)NR²²R²³; —NR²²R²³; -cyano; —COOH;        —COOR²⁰; —C(O)NR²²R²³; and —C(O)R²¹;    -   each Z is independently selected from halogen; —OH; —OR¹⁰; —SH;        —SR¹⁰; —S(O)R¹¹; —S(O)₂R¹¹; —SO₂NR¹²R¹³; trifluoromethyl;        trifluoromethoxy; nitro; —NHC(O)R¹⁰; —NHS(O)₂R¹⁰;        —NHC(O)NR¹²R¹³; —NR¹⁰C(O)R¹⁰; —NR¹⁰S(O)₂R¹⁰; —NR¹⁰C(O)NR¹²R¹³;        —NR¹²R¹³; -cyano; —COOH; —COOR¹⁰; —C(O)NR¹²R¹³; and —C(O)R¹¹;    -   each Z¹ is independently selected from hydrogen; alkyl; and Z²;    -   each Z² is independently selected from halogen; —OH; —OR²⁰; —SH;        —SR²⁰; —S(O)R²¹; —S(O)₂R²¹; —SO₂NR²²R²³; trifluoromethyl;        trifluoromethoxy; nitro; —NHC(O)R²⁰; —NHS(O)₂R²⁰;        —NHC(O)NR²²R²³; —NR²⁰C(O)R²⁰; —NR²⁰S(O)₂R²⁰; —NR²⁰C(O)NR²²R²³;        —NR²²R²³; -cyano; —COOH; —COOR²⁰; —C(O)NR²²R²³; and —C(O)R²¹;    -   each R¹⁰ is independently selected from alkyl; alkenyl; alkynyl;        aryl; heterocycle; arylalkylene; arylalkenylene; arylalkynylene;        heterocycle-alkylene; heterocycle-alkenylene and        heterocycle-alkynylene;    -   each R¹⁰¹ is independently selected from hydrogen and R¹⁰;    -   each R¹¹ is independently selected from hydroxyl; alkyl;        alkenyl; alkynyl; aryl; heterocycle; arylalkylene;        arylalkenylene; arylalkynylene; heterocycle-alkylene;        heterocycle-alkenylene and heterocycle-alkynylene;    -   each R¹² and R¹³ is independently selected from hydrogen; alkyl;        alkenyl; alkynyl; aryl; heterocycle; arylalkylene;        arylalkenylene; arylalkynylene; heterocycle-alkylene;        heterocycle-alkenylene and heterocycle-alkynylene;        -   and wherein R¹² and R¹³ can be taken together in order to            form a (4-, 5-, 6-, or 7-membered) heterocycle which can be            unsubstituted or substituted;    -   each R²⁰ is independently selected from alkyl; alkenyl; and        alkynyl;    -   each R²¹ is independently selected from hydroxyl; alkyl;        alkenyl; and alkynyl;    -   each R²² and R²³ is independently selected from hydrogen; alkyl;        alkenyl; and alkynyl;        -   and wherein R²² and R²³ can be taken together in order to            form a (4-, 5-, 6-, or 7-membered) non-aromatic heterocycle            which can be unsubstituted or substituted.

According to an embodiment, the present invention provides compounds ofFormula (A1) or (AA1), wherein

-   -   one of X¹, X², X³, X⁴ and X⁵ is selected from CW; whereby W is

while each of the other of X¹, X², X³, X⁴ and X⁵ is independentlyselected from CZ¹; N; and NR¹⁰¹; wherein maximally three of X¹, X², X³,X⁴ and X⁵ are independently selected from N; and NR¹⁰¹; Preferably oneof X¹, X², X³, X⁴ and X⁵ is selected from CW; whereby W is

while each of the other of X¹, X², X³, X⁴ and X⁵ is independentlyselected from CZ¹; and N; wherein maximally three of X¹, X², X³, X⁴ andX⁵ are independently selected from N; and NR¹⁰¹;

-   -   E is selected from CR³; and N; preferably E is CR³,    -   each R¹, R⁴ and R⁶ is independently selected from hydrogen;        halogen; —OH; —OR¹⁰; —SH; —SR¹⁰; —S(O)R¹¹; —S(O)₂R¹¹;        —SO₂NR¹²R¹³; trifluoromethyl; trifluoromethoxy; nitro;        —NHC(O)R¹⁰; —NHS(O)₂R¹⁰; —NHC(O)NR¹²R¹³; —NR¹⁰C(O)R¹⁰;        —NR¹⁰S(O)₂R¹⁰; —NR¹⁰C(O)NR¹²R¹³; —NR¹²R¹³; -cyano; —COOH;        —COOR¹⁰; —C(O)NR¹²R¹³; —C(O)R¹¹; alkyl; alkenyl; alkynyl; aryl;        heterocycle; arylalkylene; arylalkenylene; arylalkynylene;        heterocycle-alkylene; heterocycle-alkenylene; and        heterocycle-alkynylene; preferably each R¹, R⁴ and R⁶ is        independently selected from hydrogen; halogen; —OH; —OR¹⁰; —SH;        —SR¹⁰; —S(O)R¹¹; —S(O)₂R¹¹; —SO₂NR¹²R¹³; trifluoromethyl;        trifluoromethoxy; nitro; —NHC(O)R¹⁰; —NHS(O)₂R¹⁰;        —NHC(O)NR¹²R¹³; —NR¹⁰C(O)R¹⁰; —NR¹⁰S(O)₂R¹⁰; —NR¹⁰C(O)NR¹²R¹³;        —NR¹²R¹³; -cyano; —COOH; —COOR¹⁰; —C(O)NR¹²R¹³; —C(O)R¹¹;        C₁₋₆alkyl; C₂₋₆alkenyl; C₂₋₆alkynyl; C₆₋₁₀aryl; heterocycle;        C₆₋₁₀arylC₁₋₆alkylene; C₆₋₁₀arylC₂₋₆alkenylene;        C₆₋₁₀arylC₂₋₆alkynylene; heterocycle-C₁₋₆alkylene;        heterocycle-C₂₋₆alkenylene; and heterocycle-C₂₋₆alkynylene;        preferably each R¹, R⁴ and R⁶ is independently selected from        hydrogen; halogen; —OH; —OR¹⁰; —SH; trifluoromethyl;        trifluoromethoxy; nitro; —NR¹²R¹³; -cyano; —COOH; —COOR¹⁰;        C₁₋₆alkyl; C₆₋₁₀aryl; heterocycle; C₆₋₁₀arylC₁₋₆alkylene;        heterocycle-C₁₋₆alkylene; preferably each R¹, R⁴ and R⁶ is        independently selected from hydrogen; halogen; —OH; —OC₁₋₄alkyl;        trifluoromethyl; trifluoromethoxy; -cyano; C₁₋₄alkyl; C₆aryl;        C₆arylC₁₋₆alkylene; preferably each R¹, R⁴ and R⁶ is        independently selected from hydrogen; halogen; —OH; methoxy;        trifluoromethyl; trifluoromethoxy; -cyano; C₁₋₄alkyl; C₆aryl;        preferably each R¹, R⁴ and R⁶ is independently selected from        hydrogen; halogen; —OH; trifluoromethyl; C₁₋₂alkyl; preferably        each R¹, R⁴ and R⁶ is independently selected from hydrogen;        fluoro; or chloro; preferably each R¹, R⁴ and R⁶ is        independently hydrogen;    -   R³ is selected from hydrogen; halogen; —OH; —OR¹⁰; —SH; —SR¹⁰;        —S(O)R¹¹; —S(O)₂R¹¹; —SO₂NR¹²R¹³; trifluoromethyl;        trifluoromethoxy; nitro; —NHC(O)R¹⁰; —NHS(O)₂R¹⁰;        —NHC(O)NR¹²R¹³; —NR¹⁰C(O)R¹⁰; —NR¹⁰S(O)₂R¹⁰; —NR¹⁰C(O)NR¹²R¹³;        —NR¹²R¹³; -cyano; —COOH; —COOR¹⁰; —C(O)NR¹²R¹³; —C(O)R¹¹; alkyl;        alkenyl; alkynyl; aryl; heterocycle; arylalkylene;        arylalkenylene; arylalkynylene; heterocycle-alkylene;        heterocycle-alkenylene; and heterocycle-alkynylene; preferably        R³ is selected from hydrogen; halogen; —OH; —OR¹⁰; —SH; —SR¹⁰;        —S(O)R¹¹; —S(O)₂R¹¹; —SO₂NR¹²R¹³; trifluoromethyl;        trifluoromethoxy; nitro; —NHC(O)R¹⁰; —NHS(O)₂R¹⁰;        —NHC(O)NR¹²R¹³; —NR¹⁰C(O)R¹⁰; —NR¹⁰S(O)₂R¹⁰; —NR¹⁰C(O)NR¹²R¹³;        —NR¹²R¹³; -cyano; —COOH; —COOR¹⁰; —C(O)NR¹²R¹³; —C(O)R¹¹;        C₁₋₆alkyl; C₂₋₆alkenyl; C₂₋₆alkynyl; C₆₋₁₀aryl; heterocycle;        C₆₋₁₀arylC₁₋₆alkylene; C₆₋₁₀arylC₂₋₆alkenylene;        C₆₋₁₀arylC₂₋₆alkynylene; heterocycle-C₁₋₆alkylene;        heterocycle-C₂₋₆alkenylene; and heterocycle-C₂₋₆alkynylene;        preferably R³ is selected from hydrogen; halogen; —OH; —OR¹⁰;        —SH; trifluoromethyl; trifluoromethoxy; nitro; —NR¹²R¹³; -cyano;        —COOH; —COOR¹⁰; C₁₋₆alkyl; C₆₋₁₀aryl; heterocycle;        C₆₋₁₀arylC₁₋₆alkylene; heterocycle-C₁₋₆alkylene; preferably R³        is selected from hydrogen; halogen; —OH; —OC₁₋₄alkyl;        trifluoromethyl; trifluoromethoxy; -cyano; C₁₋₄alkyl; C₆aryl;        C₆arylC₁₋₆alkylene; preferably R³ is selected from hydrogen;        halogen; —OH; methoxy; trifluoromethyl; trifluoromethoxy;        -cyano; C₁₋₄alkyl; C₆aryl; preferably R³ is selected from        hydrogen; halogen; —OH; trifluoromethyl; C₁₋₂alkyl; preferably        R³ is selected from hydrogen;    -   R² is selected from hydrogen; alkyl; alkenyl; and alkynyl;        preferably R² is selected from hydrogen; C₁₋₆alkyl; C₂₋₆alkenyl;        and C₂₋₆alkynyl; preferably R² is selected from hydrogen; or        C₁₋₆alkyl; preferably R² is hydrogen;    -   R⁵ is selected from halogen; —OH; —OR¹⁰; —SH; —SR¹⁰; —S(O)R¹¹;        —S(O)₂R¹¹; —SO₂NR¹²R¹³; trifluoromethyl; trifluoromethoxy;        nitro; —NHC(O)R¹⁰; —NHS(O)₂R¹⁰; —NHC(O)NR¹²R¹³; —NR¹⁰C(O)R¹⁰;        —NR¹⁰S(O)₂R¹⁰; —NR¹⁰C(O)NR¹²R¹³; —NR¹²R¹³; -cyano; —COOH;        —COOR¹⁰; —C(O)NR¹²R¹³; —C(O)R¹¹; alkyl; alkenyl; alkynyl; aryl;        heterocycle; arylalkylene; arylalkenylene; arylalkynylene;        heterocycle-alkylene; heterocycle-alkenylene; and        heterocycle-alkynylene; preferably R⁵ is selected from halogen;        —OH; —OR¹⁰; —SH; —SR¹⁰; —S(O)R¹¹; —S(O)₂R¹¹; —SO₂NR¹²R¹³;        trifluoromethyl; trifluoromethoxy; nitro; —NHC(O)R¹⁰;        —NHS(O)₂R¹⁰; —NHC(O)NR¹²R¹³; —NR¹⁰C(O)R¹⁰; —NR¹⁰S(O)₂R¹⁰,        —NR¹⁰C(O)NR¹²R¹³; —NR¹²R¹³; -cyano; —COOH; —COOR¹⁰;        —C(O)NR¹²R¹³; —C(O)R¹¹; C₁₋₆alkyl; C₂₋₆alkenyl; C₂₋₆alkynyl;        C₆₋₁₀aryl; heterocycle; C₆₋₁₀arylC₁₋₆alkylene;        C₆₋₁₀arylC₂₋₆alkenylene; C₆₋₁₀arylC₂₋₆alkynylene;        heterocycle-C₁₋₆alkylene; heterocycle-C₂₋₆alkenylene; and        heterocycle-C₂₋₆alkynylene; preferably R⁵ is selected from        halogen; —OH; —OR¹⁰; —SH; —SR¹⁰; trifluoromethyl;        trifluoromethoxy; nitro; —NR¹²R¹³; -cyano; —COOH; —COOR¹⁰;        —C(O)R¹¹; alkyl; aryl; heterocycle; arylalkylene;        heterocycle-alkylene; preferably R⁵ is selected from halogen;        —OH; —OR¹⁰; —SH; —SR¹⁰; trifluoromethyl; trifluoromethoxy;        nitro; —NR¹²R¹³; -cyano; —COOH; —COOR¹⁰; —C(O)C₁₋₆alkyl;        C₁₋₆alkyl; C₆₋₁₀aryl; heterocycle; C₆₋₁₀arylC₁₋₆alkylene;        preferably R⁵ is selected from halogen; -cyano; —OH; —OR¹⁰; —SH;        —SR¹⁰; trifluoromethyl; trifluoromethoxy; —C(O)C₁₋₄alkyl;        —NR¹²R¹³; C₁₋₆alkyl; phenyl; morpholinyl; preferably R⁵ is        selected from chloro, fluoro; -cyano; —OH; —OR¹⁰; —SH; —SR¹⁰;        trifluoromethyl; trifluoromethoxy; C₁₋₆alkyl; phenyl;        morpholinyl; preferably R⁵ is selected from chloro, fluoro;        -cyano; —CO₁₋₄alkyl; trifluoromethyl; trifluoromethoxy;        C₁₋₆alkyl; preferably R⁵ is selected from chloro, fluoro, or        methyl;    -   n is selected from 1; 0; and 2; preferably n is 1 or 0;        preferably n is 1;    -   each of Y¹, Y², Y³, Y⁴ and Y⁵ is independently selected from        CZ¹; N; NR¹⁰¹; and CO; wherein at least two of Y¹, Y², Y³, Y⁴        and Y⁵ are selected from CZ¹; preferably each of Y¹, Y², Y³, Y⁴        and Y⁵ is independently selected from CZ¹; or N; wherein at        least two of Y¹, Y², Y³, Y⁴ and Y⁵ are selected from CZ¹;        preferably each of Y¹, Y², Y³, Y⁴ and Y⁵ is independently        selected from CZ¹; or N; wherein at least three of Y¹, Y², Y³,        Y⁴ and Y⁵ are selected from CZ¹; preferably with Z¹ being        selected from hydrogen, alkyl or Z², and Z² is halogen;    -   B represents a cyclic structure selected from aryl; cycloalkyl;        cycloalkenyl; cycloalkynyl; and heterocycle; preferably B is        selected from aryl; cycloalkyl; and heterocycle; preferably B is        selected from aryl; or heterocycle; preferably B is selected        from C₆₋₁₀aryl; or heterocycle; B is selected from C₆₋₁₀aryl;        heteroaryl or morpholinyl; preferably B is selected from phenyl,        pyridyl, dihydroypyridyl, piperidyl, thiazolyl,        tetrahydrothiophenyl, sulfur oxidized tetrahydrothiophenyl,        furanyl, thienyl, pyrrolyl, pyrazolyl, imidazolyl, tetrazolyl,        benzofuranyl, thianaphthalenyl, indolyl, indolenyl, quinolinyl,        isoquinolinyl, benzimidazolyl, piperidinyl, 4-piperidonyl,        pyrrolidinyl, 2-pyrrolidonyl, pyrrolinyl, tetrahydrofuranyl,        bis-tetrahydrofuranyl, tetrahydropyranyl, bis-tetrahydropyranyl,        tetrahydroquinolinyl, tetrahydroisoquinolinyl,        decahydroquinolinyl, octahydroisoquinolinyl, azocinyl,        triazinyl, 6H-1,2,5-thiadiazinyl, 2H,6H-1,5,2-dithiazinyl,        thianthrenyl, pyranyl, isobenzofuranyl, chromenyl, xanthenyl,        phenoxathinyl, 2H-pyrrolyl, isothiazolyl, isoxazolyl, pyrazinyl,        pyridazinyl, indolizinyl, isoindolyl, 3H-indolyl, 1H-indazoly,        purinyl, 4H-quinolizinyl, phthalazinyl, naphthyridinyl,        quinoxalinyl, quinazolinyl, cinnolinyl, pteridinyl,        4aH-carbazolyl, carbazolyl, β-carbolinyl, phenanthridinyl,        acridinyl, pyrimidinyl, phenanthrolinyl, phenazinyl,        phenothiazinyl, furazanyl, phenoxazinyl, isochromanyl,        chromanyl, imidazolidinyl, imidazolinyl, pyrazolidinyl,        pyrazolinyl, piperazinyl, indolinyl, isoindolinyl,        quinuclidinyl, morpholinyl, oxazolidinyl, benzotriazolyl,        benzisoxazolyl, oxindolyl, benzoxazolinyl, benzothienyl,        benzothiazolyl or isatinoyl; preferably B is selected from        phenyl, pyridyl, dihydroypyridyl, piperidyl, thiazolyl,        tetrahydrothiophenyl, sulfur oxidized tetrahydrothiophenyl,        furanyl, thienyl, pyrrolyl, pyrazolyl, imidazolyl, tetrazolyl,        benzofuranyl, thianaphthalenyl, indolyl, indolenyl, quinolinyl,        isoquinolinyl, benzimidazolyl, piperidinyl, 4-piperidonyl,        pyrrolidinyl, 2-pyrrolidonyl, pyrrolinyl, tetrahydrofuranyl,        bis-tetrahydrofuranyl, tetrahydropyranyl, bis-tetrahydropyranyl,        pyranyl, 2H-pyrrolyl, pyrazinyl, pyridazinyl, indolizinyl,        isoindolyl, 3H-indolyl, 1H-indazoly, purinyl, pyrimidinyl;        preferably B is selected from phenyl, pyridyl, piperidyl,        furanyl, thienyl, pyrazolyl, pyrazinyl, oxazolyl, imidazolyl,        pyrrolidinyl; preferably B is selected from phenyl, furanyl, or        thienyl;    -   m is selected from 0; 1; 2; 3; 4 and 5; preferably m is 0, 1, 2        or 3; preferably m is 0, 1 or 2, preferably m is 0 or 1;    -   each R⁸ is independently selected from hydrogen; halogen; alkyl;        alkenyl; alkynyl; —OH; —OR²⁰; —SH; trifluoromethyl;        trifluoromethoxy; nitro; -cyano; —COOH; —COOR²⁰; —C(O)NR²²R²³;        and —C(O)R²¹; preferably each R⁸ is independently selected from        hydrogen; halogen; alkyl; alkenyl; alkynyl; —OH; —OR²⁰; —SH;        trifluoromethyl; trifluoromethoxy; nitro; -cyano; —COOH;        —COOR²⁰; —C(O)NR²²R²³; and —C(O)R²¹; preferably each R⁸ is        independently selected from hydrogen; halogen; alkyl; —OH;        —OR²⁰; —SH; trifluoromethyl; trifluoromethoxy; nitro; -cyano;        preferably each R⁸ is independently selected from hydrogen;        halogen; alkyl; —OR²⁰; trifluoromethyl; trifluoromethoxy;        -cyano; wherein R²⁰ is alkyl; preferably each R⁸ is        independently selected from hydrogen; halogen; C₁₋₆alkyl; —OR²⁰;        trifluoromethyl; trifluoromethoxy; -cyano; wherein R²⁰ is        C₁₋₆alkyl; preferably each R⁸ is independently selected from        hydrogen; halogen; C₁₋₄alkyl; —OR²⁰; trifluoromethyl; -cyano;        wherein R²⁰ is C₁₋₂alkyl; preferably each R⁸ is independently        selected from hydrogen; fluoro; chloro; C₁₋₂alkyl; —OCH₃;        trifluoromethyl; -cyano;    -   each Z¹ is independently selected from hydrogen; alkyl; and Z²;        preferably each Z¹ is independently selected from hydrogen;        C₁₋₆alkyl; and Z²;    -   each Z² is independently selected from halogen; —OH; —OR²⁰; —SH;        —SR²⁰; —S(O)R²¹; —S(O)₂R²¹; —SO₂NR²²R²³; trifluoromethyl;        trifluoromethoxy; nitro; —NHC(O)R²⁰; —NHS(O)₂R²⁰;        —NHC(O)NR²²R²³; —NR²⁰C(O)R²⁰; —NR²⁰S(O)₂R²⁰; —NR²⁰C(O)NR²²R²³;        —NR²²R²³; -cyano; —COOH; —COOR²⁰; —C(O)NR²²R²³; and —C(O)R²¹;        preferably each Z² is independently selected from halogen; —OH;        —OR²⁰; —SH; —SR²⁰; —S(O)R²¹; —S(O)₂R²¹; —SO₂NR²²R²³;        trifluoromethyl; trifluoromethoxy; nitro; —NR²²R²³; -cyano;        —COOH; —COOR²⁰; and —C(O)R²¹; preferably each Z² is        independently selected from halogen; —OH; —OR²⁰; —SH;        trifluoromethyl; trifluoromethoxy; —NR²²R²³; -cyano; —COOH;        —COOR²⁰; and —C(O)R²¹; preferably each Z² is independently        selected from halogen; —OH; —OC₁₋₆alkyl; trifluoromethyl;        trifluoromethoxy; -cyano; preferably each Z² is independently        selected from fluoro; chloro; —OH; —OC₁₋₃alkyl; trifluoromethyl;        trifluoromethoxy; -cyano;    -   each R¹⁰ is independently selected from alkyl; alkenyl; alkynyl;        aryl; heterocycle; arylalkylene; arylalkenylene; arylalkynylene;        heterocycle-alkylene; heterocycle-alkenylene and        heterocycle-alkynylene; preferably each R¹⁰ is independently        selected from alkyl; aryl; heterocycle; arylalkylene;        heterocycle-alkylene; preferably each R¹⁰ is independently        selected from C₁₋₆alkyl; C₆₋₁₀aryl; heterocycle;        C₆₋₁₀arylC₁₋₆alkylene; preferably each R¹⁰ is independently        C₁₋₆alkyl;    -   each R¹⁰¹ is independently selected from hydrogen and R¹⁰;    -   each R¹¹ is independently selected from hydroxyl; alkyl;        alkenyl; alkynyl; aryl; heterocycle; arylalkylene;        arylalkenylene; arylalkynylene; heterocycle-alkylene;        heterocycle-alkenylene and heterocycle-alkynylene; preferably        each R¹¹ is independently selected from hydroxyl, alkyl; aryl;        heterocycle; arylalkylene; heterocycle-alkylene; preferably each        R¹¹ is independently selected from hydroxyl; C₁₋₆alkyl;        C₆₋₁₀aryl; heterocycle; C₆₋₁₀arylC₁₋₆alkylene; preferably each        R¹¹ is independently from hydroxyl or C₁₋₆alkyl;    -   each R¹² and R¹³ is independently selected from hydrogen; alkyl;        alkenyl; alkynyl; aryl; heterocycle; arylalkylene;        arylalkenylene; arylalkynylene; heterocycle-alkylene;        heterocycle-alkenylene and heterocycle-alkynylene; and wherein        R¹² and R¹³ can be taken together in order to form a (4-, 5-,        6-, or 7-membered) heterocycle which can be unsubstituted or        substituted; preferably each R¹² and R¹³ is independently        selected from hydrogen; alkyl; aryl; heterocycle; arylalkylene;        heterocycle-alkylene; and wherein R¹² and R¹³ can be taken        together in order to form a 4-, 5-, or 6-, membered heterocycle;        preferably each R¹² and R¹³ is independently selected from        hydrogen; alkyl; aryl; heterocycle; arylalkylene; preferably        each R¹² and R¹³ is independently selected from hydrogen;        C₁₋₆alkyl; C₆₋₁₀aryl; heterocycle;    -   each R²⁰ is independently selected from alkyl; alkenyl; and        alkynyl; preferably each R²⁰ is independently selected from        alkyl; preferably each R²⁰ is independently selected from        C₁₋₆alkyl; preferably each R²⁰ is independently selected from        C₁₋₄alkyl;    -   each R²¹ is independently selected from hydroxyl; alkyl;        alkenyl; and alkynyl; preferably each R²¹ is independently        selected from alkyl; preferably each R²¹ is independently        selected from C₁₋₆alkyl; preferably each R²¹ is independently        selected from C₁₋₄alkyl;    -   each R²² and R²³ is independently selected from hydrogen; alkyl;        alkenyl; and alkynyl; and wherein R²² and R²³ can be taken        together in order to form a (4-, 5-, 6-, or 7-membered)        non-aromatic heterocycle which can be unsubstituted or        substituted; preferably each R²² and R²³ is independently        selected from hydrogen; or alkyl; and wherein R²² and R²³ can be        taken together in order to form a 4-, 5-, or 6-, membered        non-aromatic heterocycle; preferably each R²² and R²³ is        independently selected from hydrogen; or alkyl; preferably each        R²² and R²³ is independently selected from hydrogen; or        C₁₋₆alkyl.        In another particular embodiment, R⁵ is selected from halogen,        methoxy, methyl, trifluoromethoxy, acetyl, phenyl, cyano and        morpholinyl. In another particular embodiment, R⁵ is selected        from halogen.

In another particular embodiment, R⁵ is selected from halogen, methoxy,methyl, trifluoromethoxy, trifluoromethyl, hydroxyl, acetyl, and cyano.In another particular embodiment, R⁵ is selected from fluoro and chloro.

In a particular embodiment, E is CR³.

In a particular embodiment, each R¹, R³, R⁴, and R⁶ is independentlyselected from hydrogen; halogen; —OH; —OR¹⁰; —SH; —SR¹⁰; —S(O)R¹¹;—S(O)₂R¹¹; —SO₂NR¹²R¹³; trifluoromethyl; trifluoromethoxy; nitro;—NHC(O)R¹⁰; —NHS(O)₂R¹⁰; —NHC(O)NR¹²R¹³; —NR¹⁰C(O)R¹⁰; —NR¹⁰S(O)₂R¹⁰;—NR¹⁰C(O)NR¹²R¹³; —NR¹²R¹³; -cyano; —COOH; —COOR¹⁰; —C(O)NR¹²R¹³;—C(O)R¹¹; alkyl; alkenyl; and alkynyl. More in particular, each R¹, R³,R⁴, and R⁶ is independently selected from hydrogen; halogen; —OH; —OR¹⁰;—SH; —SR¹⁰; trifluoromethyl; trifluoromethoxy; nitro; alkyl; alkenyl;and alkynyl. Yet more in particular embodiment, each of R¹, R³, R⁴ andR⁶ is independently selected from hydrogen, halogen, —OH, methoxy, andmethyl. In yet another particular embodiment, each of R¹, R³, R⁴ and R⁶is independently selected from hydrogen and halogen, more in particulareach of R¹, R³, R⁴ and R⁶ is hydrogen.

In another particular embodiment, R¹ is hydrogen or alkyl, more inparticular is hydrogen. In another particular embodiment, R² is hydrogenor alkyl, yet more in particular is hydrogen. In another particularembodiment, R³ is hydrogen. In another particular embodiment, R⁴ ishydrogen or halogen. In another particular embodiment, R⁴ is hydrogen.In another particular embodiment, R⁶ is hydrogen. In another particularembodiment, R³, R⁴ and R⁶ are hydrogen.

In another particular embodiment, R² is independently selected fromhydrogen and methyl, yet more in particular is hydrogen.

In a particular embodiment, n is 1.

In a particular embodiment of the present invention and of all formulasherein, each of Y¹, Y², Y³, Y⁴ and Y⁵ is independently selected fromCZ¹; N; and NR¹⁰¹. In another particular embodiment, each of Y¹, Y², Y³,Y⁴ and Y⁵ is independently selected from CZ¹; N; and NR¹⁰¹ and form aring selected from phenyl, pyridyl, pyridazyl, pyrazinyl and pyrimidyl.In yet another particular embodiment, each of Y¹, Y², Y³, Y⁴ and Y⁵ isCZ¹ and form a phenyl ring.

In a particular embodiment of the present invention and of all formulasherein, each of Y¹, Y², Y³ is CZ¹ and each of Y⁴ and Y⁵ is N.

In a particular embodiment of the present invention and of all formulasherein, each of Y¹, Y², Y³ and Y⁵ is CZ¹ and each Y⁴ is N.

In a particular embodiment of the present invention and of all formulasherein, each of Y¹, Y², Y⁴ and Y⁵ is CZ¹ and each Y³ is N.

In a particular embodiment of the present invention and of all formulasherein, each Z¹ is hydrogen.

In a particular embodiment, B is selected from C₃₋₈cycloalkyl;C₅₋₈cycloalkenyl; C₆₋₁₀aryl; or heterocycle; more particularly B isselected from C₃₋₈cycloalkyl; C₆₋₁₀aryl; or pyridyl, dihydroypyridyl,piperidyl, thiazolyl, tetrahydrothiophenyl, sulfur oxidizedtetrahydrothiophenyl, furanyl, thienyl, pyrrolyl, pyrazolyl, imidazolyl,tetrazolyl, benzofuranyl, thianaphthalenyl, indolyl, indolenyl,quinolinyl, isoquinolinyl, benzimidazolyl, piperidinyl, 4-piperidonyl,pyrrolidinyl, 2-pyrrolidonyl, pyrrolinyl, tetrahydrofuranyl,bis-tetrahydrofuranyl, tetrahydropyranyl, bis-tetrahydropyranyl,tetrahydroquinolinyl, tetrahydroisoquinolinyl, decahydroquinolinyl,octahydroisoquinolinyl, azocinyl, triazinyl, 6H-1,2,5-thiadiazinyl,2H,6H-1,5,2-dithiazinyl, thianthrenyl, pyranyl, isobenzofuranyl,chromenyl, xanthenyl, phenoxathinyl, 2H-pyrrolyl, isothiazolyl,isoxazolyl, pyrazinyl, pyridazinyl, indolizinyl, isoindolyl, 3H-indolyl,1H-indazoly, purinyl, 4H-quinolizinyl, phthalazinyl, naphthyridinyl,quinoxalinyl, quinazolinyl, cinnolinyl, pteridinyl, 4aH-carbazolyl,carbazolyl, fl-carbolinyl, phenanthridinyl, acridinyl, pyrimidinyl,phenanthrolinyl, phenazinyl, phenothiazinyl, furazanyl, phenoxazinyl,isochromanyl, chromanyl, imidazolidinyl, imidazolinyl, pyrazolidinyl,pyrazolinyl, piperazinyl, indolinyl, isoindolinyl, quinuclidinyl,morpholinyl, oxazolidinyl, benzotriazolyl, benzisoxazolyl, oxindolyl,benzoxazolinyl, benzothienyl, benzothiazolyl or isatinoyl; yet moreparticularly B is selected from C₃₋₆cycloalkyl; C₆₋₁₀aryl; or pyridyl,dihydroypyridyl, piperidyl, thiazolyl, tetrahydrothiophenyl, furanyl,thienyl, pyrrolyl, pyrazolyl, imidazolyl, tetrazolyl, benzofuranyl,indolyl, indolenyl, quinolinyl, isoquinolinyl, benzimidazolyl,piperidinyl, 4-piperidonyl, pyrrolidinyl, 2-pyrrolidonyl, pyrrolinyl,tetrahydrofuranyl, tetrahydropyranyl, tetrahydroquinolinyl,tetrahydroisoquinolinyl, decahydroquinolinyl, octahydroisoquinolinyl,azocinyl, triazinyl, 6H-1,2,5-thiadiazinyl, 2H,6H-1,5,2-dithiazinyl,thianthrenyl, pyranyl, isobenzofuranyl, 2H-pyrrolyl, isothiazolyl,isoxazolyl, pyrazinyl, pyridazinyl, indolizinyl, isoindolyl, 3H-indolyl,1H-indazoly, purinyl, 4H-quinolizinyl, phthalazinyl, naphthyridinyl,quinoxalinyl, quinazolinyl, cinnolinyl, 4aH-carbazolyl, carbazolyl,fl-carbolinyl, phenanthridinyl, acridinyl, pyrimidinyl, phenanthrolinyl,phenazinyl, phenothiazinyl, furazanyl, phenoxazinyl, isochromanyl,chromanyl, imidazolidinyl, imidazolinyl, pyrazolidinyl, pyrazolinyl,piperazinyl, indolinyl, isoindolinyl, quinuclidinyl, morpholinyl,oxazolidinyl, benzotriazolyl, benzisoxazolyl, oxindolyl, benzoxazolinyl,benzothienyl, benzothiazolyl or isatinoyl; still more particularly B isselected from C₃₋₆cycloalkyl; phenyl, naphthyl, pyridyl, piperidyl,thiazolyl, furanyl, thienyl, pyrrolyl, pyrazolyl, imidazolyl,tetrazolyl, benzofuranyl, indolyl, indolenyl, quinolinyl, isoquinolinyl,benzimidazolyl, piperidinyl, 4-piperidonyl, pyrrolidinyl,2-pyrrolidonyl, pyrrolinyl, triazinyl, pyranyl, isobenzofuranyl,2H-pyrrolyl, isothiazolyl, isoxazolyl, pyrazinyl, pyridazinyl,indolizinyl, isoindolyl, 3H-indolyl, 1H-indazoly, purinyl, pyrimidinyl,furazanyl, imidazolidinyl, imidazolinyl, pyrazolidinyl, pyrazolinyl,piperazinyl, indolinyl, isoindolinyl, quinuclidinyl, morpholinyl,oxazolidinyl, benzotriazolyl, benzisoxazolyl, oxindolyl, benzoxazolinyl,benzothienyl, benzothiazolyl or isatinoyl. In another particularembodiment, B is independently selected from aryl and heterocycle. Yetmore in particular, B is selected from aryl and heteroaryl. Still morein particular, B is selected from phenyl, thienyl, furanyl or pyridyl.Yet more in particular, B is phenyl.

In another particular embodiment, R⁸ is not selected from —NHC(O)R¹⁰. Inanother particular embodiment, R⁸ is selected from hydrogen; halogen;alkyl; alkenyl; alkynyl; —OH; —OR¹⁰; —SH; —SR¹⁰; —S(O)R¹¹; —S(O)₂R¹¹;—SO₂NR¹²R¹³; trifluoromethyl; trifluoromethoxy; nitro; —NHS(O)₂R¹⁰;—NHC(O)NR¹²R¹³; —NR¹⁰C(O)R¹⁰; —NR¹⁰S(O)₂R¹⁰; —NR¹⁰C(O)NR¹²R¹³; —NR¹²R¹³;-cyano; —COOH; —COOR¹⁰; —C(O)NR¹²R¹³; —C(O)R¹¹; wherein said alkyl,alkenyl and alkynyl optionally includes one or more heteroatoms, saidheteroatoms being selected from the atoms O, S and N; and wherein saidalkyl, alkenyl and alkynyl can be unsubstituted or substituted with Z;and wherein a carbon atom or heteroatom of said alkyl, alkenyl andalkynyl, can be oxidized to form a C═S, N═O, N═S, S═O or S(O)₂.

In another particular embodiment, R⁸ is selected from hydrogen; halogen;alkyl; alkenyl; alkynyl; —OH; —OR¹⁰; —SH; —SR¹⁰; trifluoromethyl;trifluoromethoxy; —NR¹²R¹³; -cyano. In another particular embodiment, R⁸is selected from hydrogen; halogen; linear alkyl; linear alkenyl; linearalkynyl; —OH; —OR¹⁰; —SH; —SR¹⁰; trifluoromethyl; trifluoromethoxy;—NR¹²R¹³; -cyano. In another particular embodiment, R⁸ does not comprisea cyclic ring structure (for example selected from cyclic alkyl, cyclicalkenyl, cyclic alkynyl, aryl or heterocycle). In another particularembodiment, R⁸ is independently selected from halogen, methyl, methoxy,cyano, and trifluoromethyl. In a particular embodiment, R⁸ is halogen,yet more in particular is fluor. In a particular embodiment, each R⁸ isindependently selected from halogen; C₁₋₆alkyl; —OH; C₁₋₆alkoxy;C₁₋₆alkoxycarbonyl; trifluoromethyl; trifluoromethoxy; and cyano.

In another particular embodiment, m is selected from 0, 1 and 2.

In yet another particular embodiment, the compounds of the inventioncomprise maximally three monocyclic or cyclic fused ring systemsselected from aryl or heterocycle. In yet another particular embodiment,the compounds of the invention comprise maximally three ring systems,whereby said three ring systems consist of:

-   -   the indole or azaindole ring;    -   the six-membered ring comprising Y¹, Y², Y³, Y⁴ and Y⁵; and    -   B.

In a particular embodiment of the present invention, the compounds havea structure according to the formulas (A2), or (A3):

wherein R¹, R², R³, R⁴, R⁵, R⁶, R⁸, Y¹, Y², Y³, Y⁴, Y⁵, B, m and n havethe same meaning as that defined herein (for example in formula (A1) andthe embodiments thereof).

In a more particular embodiment the present invention therefore providescompounds according to formula (B1), (B2) or (B3),

wherein E, R¹, R², R³, R⁴, R⁵, R⁶, R⁸, Y¹, Y², Y³, Y⁴, Y⁵, B, m and nhave the same meaning as that defined herein (for example in formula A1and the embodiments thereof).

In another preferred embodiment, the compounds have a structureaccording to formula (C1), (C2) or (C3);

wherein E, R¹, R², R³, R⁴, R⁵, R⁶, R⁸, B, m and n have the same meaningas that defined herein (for example in formula A1 and the embodimentsthereof).

In yet another preferred embodiment, the compounds have a structureaccording to formula (F1), (F2), (F3), (F4) or (F5),

wherein E, R¹, R², R³, R⁴, R⁵, R⁶, R⁸, Y¹, Y², Y³, Y⁴, Y⁵, m and n havethe same meaning as that defined herein (for example in formula A1 andthe embodiments thereof).

In a particular embodiment of the present invention, the compounds havea structure according to the formulas (AA1), (A1), (A2), (A3), (B1),(B2), (B3), (C1), (C2), (C3), (F1), (F2), (F3), (F4) or (F5) or anysubgroup thereof, wherein n is 1.

In another particular embodiment of the present invention, the compoundshave a structure according to the formulas (AA1), (A1), (A2), (A3),(B1), (B2), (B3), (C1), (C2), (C3), (F1), (F2), (F3), (F4) or (F5) orany subgroup thereof, whereby R² is H. In another particular embodimentof the present invention, the compounds have a structure according tothe formulas (AA1), (A1), (A2), (A3), (B1), (B2), (B3), (C1), (C2),(C3), (F1), (F2), (F3), (F4) or (F5) or any subgroup thereof, whereby R³is H.

In another particular embodiment of the present invention, the compoundshave a structure according to the formulas (AA1), (A1), (A2), (A3),(B1), (B2), (B3), (C1), (C2), (C3), (F1), (F2), (F3), (F4) or (F5) orany subgroup thereof, wherein B is aryl or heteroaryl (yet more inparticular is phenyl, thienyl, furanyl or pyridyl) and R⁸ is selectedfrom hydrogen, halogen, —OH, cyano, C₁₋₆alkoxy, trifluoromethyl;trifluoromethoxy. In another particular embodiment of the presentinvention, the compounds have a structure according to the formulasherein, whereby R⁸ is selected from hydrogen and halogen.

In a particular embodiment of the present invention, the compounds havea structure according to the formulas (AA1), (A1), (A2), (A3), (B1),(B2), (B3), (C1), (C2), (C3), (F1), (F2), (F3), (F4) or (F5) or anysubgroup thereof, wherein B is aryl and R⁸ is selected from hydrogen,halogen, —OH, cyano, C₁₋₆alkoxy, trifluoromethyl; trifluoromethoxy.

In a particular embodiment of the present invention, the compounds havea structure according to the formulas (AA1), (A1), (A2), (A3), (B1),(B2), (B3), (C1), (C2), (C3), (F1), (F2), (F3), (F4) or (F5) or anysubgroup thereof, wherein B is aryl and R⁸ is selected from hydrogen,halogen, cyano, C₁₋₆alkoxy, trifluoromethyl; trifluoromethoxy.

In another particular embodiment of the present invention, the compoundshave a structure according to the formulas (AA1), (A1), (A2), (A3),(B1), (B2), (B3), (C1), (C2), (C3), (F1), (F2), (F3), (F4) or (F5) orany subgroup thereof, whereby the cycle B is phenyl.

In another particular embodiment of the present invention, the compoundshave a structure according to the formulas herein, whereby R¹, R³, R⁴and R⁶ are hydrogen.

In another particular embodiment of the present invention, the compoundshave a structure according to the formulas herein, wherein R¹, R², R³,R⁴ and R⁶ are hydrogen.

A particular embodiment of the invention relates to compounds with astructure according to formula (G1), (G2), (G3), (G4), (G5), (G6), (G7),or (G8):

whereby all the remaining variables are as in formula (A1) or otherformula or all embodiments described herein.

Another particular embodiment of the invention relates to compounds witha structure according to formula (H1), (H2), (H3) or (H4)

whereby all the remaining variables are as in formula (A1) or otherformula or all embodiments described herein.

Another particular embodiment of the invention relates to compounds witha structure according to formula (I1), (I2), (I3), or (I4)

wherein

-   -   R⁴ is selected from hydrogen and halogen;    -   R⁵ is selected from halogen; —OH; —OR¹⁰; trifluoromethyl;        trifluoromethoxy; cyano; —C(O)R¹¹; and C₁₋₆alkyl;    -   n is selected from 0; 1; and 2;    -   B represents a cyclic structure selected from C₃₋₈cycloalkyl;        C₆₋₁₀aryl; and heterocycle;    -   m is selected from 0; 1; and 2;    -   each R⁸ is independently selected from halogen; C₁₋₆alkyl; OH;        C₁₋₆alkoxy; —COOR²⁰; trifluoromethyl; trifluoromethoxy; and        cyano;    -   each R¹⁰ is C₁₋₆alkyl;    -   each R¹¹ is C₁₋₆alkyl;    -   each R²⁰ is C₁₋₆alkyl;    -   with the proviso that in formula (I1) when B is ortho-phenyl,        then m is 1 or 2; and isomers (in particular stereoisomers,        enantiomers or tautomers), solvates, hydrates, salts (in        particular pharmaceutically acceptable salts) or prodrugs        thereof.

The term “ortho-phenyl” present in the proviso within the definition of“B” and for formula (I1), indicates that a phenyl ring is located inposition ortho versus the phenyl ring depicted in formula (I1).

Another particular embodiment of the invention relates to compounds witha structure according to formula (J1), (J2), (J3), or (J4)

wherein

-   -   R⁴ is selected from hydrogen and halogen;    -   R⁵ is selected from halogen; —OH; —OR¹⁰; trifluoromethyl;        trifluoromethoxy; cyano; —C(O)R¹¹; and C₁₋₆alkyl;    -   B represents a cyclic structure selected from C₃₋₈cycloalkyl;        C₆₋₁₀aryl; and heterocycle;    -   m is selected from 0; 1; and 2;    -   each R⁸ is independently selected from halogen; C₁₋₈alkyl; OH;        C₁₋₆alkoxy; —COOR²⁰; trifluoromethyl; trifluoromethoxy; and        cyano;    -   each R¹⁰ is C₁₋₆alkyl;    -   each R¹¹ is C₁₋₆alkyl;    -   each R²⁰ is C₁₋₆alkyl;    -   with the proviso that in formula (J1) when B is ortho-phenyl,        then m is 1 or 2; and isomers (in particular stereoisomers,        enantiomers or tautomers), solvates, hydrates, salts (in        particular pharmaceutically acceptable salts) or prodrugs        thereof.

The term “ortho-phenyl” present in the proviso within the definition of“B” and for formula (J1), indicates that a phenyl ring is located inposition ortho versus the phenyl ring depicted in formula (J1).

Another particular embodiment of the invention relates to compounds witha structure according to formula (K1), (K2), (K3), or (K4)

wherein

-   -   R⁴ is selected from hydrogen and halogen;    -   R⁵ is selected from halogen; —OH; —OR¹⁰; trifluoromethyl;        trifluoromethoxy; cyano; —C(O)R¹¹; and C₁₋₆alkyl;    -   n is selected from 0; 1; and 2;    -   B is selected from C₃₋₈cycloalkyl, meta-C₆₋₁₀aryl,        para-C₆₋₁₀aryl, and heterocycle; each independently optionally        substituted with one or two R⁸ substituents; or B is an        ortho-C₆₋₁₀aryl substituted with one or two R⁸ substituents;    -   each R⁸ is independently selected from halogen; C₁₋₆alkyl; OH;        C₁₋₆alkoxy; COOR²⁰; trifluoromethyl; trifluoromethoxy; and        cyano;    -   each R¹⁰ is C₁₋₆alkyl;    -   each R¹¹ is C₁₋₆alkyl;    -   each R²⁰ is C₁₋₆alkyl;        and isomers (in particular stereoisomers, enantiomers or        tautomers), solvates, hydrates, salts (in particular        pharmaceutically acceptable salts) or prodrugs thereof.

Within the definition of “B”, the term meta-C₆₋₁₀aryl indicates that anC₆₋₁₀aryl group is located in position meta versus any one of thephenyl, piridazinyl, and pyridinyl rings depicted in formulae (K1),(K2), (K3) and (K4), respectively.

Within the definition of “B”, the term para-C₆₋₁₀aryl indicates that anC₆₋₁₀aryl group is located in position para versus any one of thephenyl, piridazinyl, and pyridinyl rings depicted in formulae (K1),(K2), (K3) and (K4), respectively.

Within the definition of “B”, the term ortho-C₆₋₁₀aryl indicates that anC₆₋₁₀aryl group is located in position ortho versus any one of thephenyl, piridazinyl, and pyridinyl rings depicted in formulae (K1),(K2), (K3) and (K4), respectively.

Another particular embodiment of the invention relates to compounds witha structure according to formula (L1), (L2), (L3), or (L4)

wherein

-   -   R⁴ is selected from hydrogen and halogen;    -   R⁵ is selected from halogen; —OH; —OR¹⁰; trifluoromethyl;        trifluoromethoxy; cyano; —C(O)R¹¹; and C₁₋₆alkyl;    -   B is selected from C₃₋₈cycloalkyl, meta-C₆₋₁₀aryl,        para-C₆₋₁₀aryl, and heterocycle; each independently optionally        substituted with one or two R⁸ substituents; or B is an        ortho-C₆₋₁₀aryl substituted with one or two R⁸ substituents;    -   each R⁸ is independently selected from halogen; C₁₋₆alkyl; OH;        C₁₋₆alkoxy; COOR²⁰; trifluoromethyl; trifluoromethoxy; and        cyano;    -   each R¹⁰ is C₁₋₆alkyl;    -   each R¹¹ is C₁₋₆alkyl;    -   each R²⁰ is C₁₋₆alkyl;        and isomers (in particular stereoisomers, enantiomers or        tautomers), solvates, hydrates, salts (in particular        pharmaceutically acceptable salts) or prodrugs thereof.

Within the definition of “B”, the term meta-C₆₋₁₀aryl indicates that anC₆₋₁₀aryl group is located in position meta versus any one of thephenyl, piridazinyl, and pyridinyl rings depicted in formulae (L1),(L2), (L3) and (L4), respectively.

Within the definition of “B”, the term para-C₆₋₁₀aryl indicates that anC₆₋₁₀aryl group is located in position para versus any one of thephenyl, piridazinyl, and pyridinyl rings depicted in formulae (L1),(L2), (L3) and (L4), respectively.

Within the definition of “B”, the term ortho-C₆₋₁₀aryl indicates that anC₆₋₁₀aryl group is located in position ortho versus any one of thephenyl, piridazinyl, and pyridinyl rings depicted in formulae (L1),(L2), (L3) and (L4), respectively.

In a particular embodiment, the compounds of the present invention areselected from the list of:

-   N-(2-(5-methoxy-1H-indol-3-yl)ethyl)biphenyl-4-carboxamide;-   N-(2-(5-chloro-1H-indol-3-yl)ethyl)biphenyl-4-carboxamide;-   N-(2-(5-fluoro-1H-indol-3-yl)ethyl)biphenyl-4-carboxamide;-   N-(2-(5-methyl-1H-indol-3-yl)ethyl)biphenyl-4-carboxamide;-   ethyl    5-amino-1-(4-(2-(5-methyl-1H-indol-3-yl)ethylcarbamoyl)phenyl)-1H-pyrazole-4-carboxylate;-   N-(2-(5-chloro-1H-indol-3-yl)ethyl)-2-morpholinoisonicotinamide;-   N-(2-(5-fluoro-1H-indol-3-yl)ethyl)-2-morpholinoisonicotinamide;-   N-(2-(5-chloro-1H-indol-3-yl)ethyl)biphenyl-2-carboxamide;-   N-(2-(5-chloro-1H-indol-3-yl)ethyl)-4-(thiophen-2-yl)benzamide;-   N-(2-(5-chloro-1H-indol-3-yl)ethyl)biphenyl-3-carboxamide;-   N-(2-(5-chloro-1H-indol-3-yl)ethyl)-2′,6′-dimethylbiphenyl-4-carboxamide;-   N-(2-(5-chloro-1H-indol-3-yl)ethyl)-4′-hydroxybiphenyl-2-carboxamide;-   N-(2-(5-chloro-1H-indol-3-yl)ethyl)-4′-hydroxybiphenyl-3-carboxamide;-   N-(2-(5-chloro-1H-indol-3-yl)ethyl)-4′-hydroxybiphenyl-4-carboxamide;-   N-(2-(5-chloro-1H-indol-3-yl)ethyl)-2′-methylbiphenyl-2-carboxamide;-   N-(2-(5-chloro-1H-indol-3-yl)ethyl)-2′-methylbiphenyl-3-carboxamide;-   N-(2-(5-chloro-1H-indol-3-yl)ethyl)-2′-methylbiphenyl-4-carboxamide;-   N-(2-(5-chloro-1H-indol-3-yl)ethyl)-3′-methylbiphenyl-2-carboxamide;-   N-(2-(5-chloro-1H-indol-3-yl)ethyl)-3′-methylbiphenyl-3-carboxamide;-   N-(2-(5-chloro-1H-indol-3-yl)ethyl)-3′-methylbiphenyl-4-carboxamide;-   N-(2-(5-chloro-1H-indol-3-yl)ethyl)-4′-methylbiphenyl-2-carboxamide;-   N-(2-(5-chloro-1H-indol-3-yl)ethyl)-4′-methylbiphenyl-3-carboxamide;-   N-(2-(5-chloro-1H-indol-3-yl)ethyl)-4′-methylbiphenyl-4-carboxamide;-   N-(2-(5-chloro-1H-indol-3-yl)ethyl)-6-morpholinonicotinamide;-   N-(2-(5-chloro-1H-indol-3-yl)ethyl)-2-(1H-pyrazol-1-yl)benzamide;-   N-(2-(5-chloro-1H-indol-3-yl)ethyl)-2′-methoxpiphenyl-2-carboxamide;-   N-(2-(5-chloro-1H-indol-3-yl)ethyl)-2′-methoxpiphenyl-3-carboxamide;-   N-(2-(5-chloro-1H-indol-3-yl)ethyl)-2′-methoxpiphenyl-4-carboxamide;-   N-(2-(5-chloro-1H-indol-3-yl)ethyl)-3′-methoxpiphenyl-2-carboxamide;-   N-(2-(5-chloro-1H-indol-3-yl)ethyl)-3′-methoxpiphenyl-3-carboxamide;-   N-(2-(5-chloro-1H-indol-3-yl)ethyl)-3′-methoxpiphenyl-4-carboxamide;-   N-(2-(5-chloro-1H-indol-3-yl)ethyl)-4′-methoxpiphenyl-2-carboxamide;-   N-(2-(5-chloro-1H-indol-3-yl)ethyl)-4′-methoxpiphenyl-3-carboxamide;-   N-(2-(5-chloro-1H-indol-3-yl)ethyl)-4′-methoxpiphenyl-4-carboxamide;-   N-(2-(5-chloro-1H-indol-3-yl)ethyl)-2′-fluorobiphenyl-2-carboxamide;-   N-(2-(5-chloro-1H-indol-3-yl)ethyl)-2′-fluorobiphenyl-3-carboxamide;-   N-(2-(5-chloro-1H-indol-3-yl)ethyl)-2′-fluorobiphenyl-4-carboxamide;-   N-(2-(5-chloro-1H-indol-3-yl)ethyl)-3′-fluorobiphenyl-2-carboxamide;-   N-(2-(5-chloro-1H-indol-3-yl)ethyl)-3′-fluorobiphenyl-4-carboxamide;-   N-(2-(5-chloro-1H-indol-3-yl)ethyl)-4′-fluorobiphenyl-2-carboxamide;-   N-(2-(5-chloro-1H-indol-3-yl)ethyl)-4′-fluorobiphenyl-3-carboxamide;-   N-(2-(5-chloro-1H-indol-3-yl)ethyl)-4′-fluorobiphenyl-4-carboxamide;-   N-(2-(5-chloro-1H-indol-3-yl)ethyl)-2′-cyanobiphenyl-3-carboxamide;-   N-(2-(5-chloro-1H-indol-3-yl)ethyl)-2′-cyanobiphenyl-4-carboxamide;-   N-(2-(5-chloro-1H-indol-3-yl)ethyl)-3-(pyridin-4-yl)benzamide;-   N-(2-(5-chloro-1H-indol-3-yl)ethyl)-4-(pyridin-4-yl)benzamide;-   N-(2-(5-chloro-1H-indol-3-yl)ethyl)-3′-fluorobiphenyl-3-carboxamide;-   N-(2-(5-chloro-1H-indol-3-yl)ethyl)-3′-cyanobiphenyl-2-carboxamide;-   N-(2-(5-chloro-1H-indol-3-yl)ethyl)-3′-cyanobiphenyl-3-carboxamide;-   N-(2-(5-chloro-1H-indol-3-yl)ethyl)-3′-cyanobiphenyl-4-carboxamide;-   N-(2-(5-chloro-1H-indol-3-yl)ethyl)-4′-cyanobiphenyl-2-carboxamide;-   N-(2-(5-chloro-1H-indol-3-yl)ethyl)-4′-cyanobiphenyl-3-carboxamide;-   N-(2-(5-chloro-1H-indol-3-yl)ethyl)-4′-cyanobiphenyl-4-carboxamide;-   2′-chloro-N-(2-(5-chloro-1H-indol-3-yl)ethyl)biphenyl-2-carboxamide;-   2′-chloro-N-(2-(5-chloro-1H-indol-3-yl)ethyl)biphenyl-3-carboxamide;-   2′-chloro-N-(2-(5-chloro-1H-indol-3-yl)ethyl)biphenyl-4-carboxamide;-   3′-chloro-N-(2-(5-chloro-1H-indol-3-yl)ethyl)biphenyl-2-carboxamide;-   3′-chloro-N-(2-(5-chloro-1H-indol-3-yl)ethyl)biphenyl-3-carboxamide;-   3′-chloro-N-(2-(5-chloro-1H-indol-3-yl)ethyl)biphenyl-4-carboxamide;-   4′-chloro-N-(2-(5-chloro-1H-indol-3-yl)ethyl)biphenyl-3-carboxamide;-   4′-chloro-N-(2-(5-chloro-1H-indol-3-yl)ethyl)biphenyl-4-carboxamide;-   N-(2-(5-chloro-1H-indol-3-yl)ethyl)-2′-(trifluoromethyl)biphenyl-4-carboxamide;-   4′-chloro-N-(2-(5-chloro-1H-indol-3-yl)ethyl)biphenyl-2-carboxamide;-   N-(2-(5-chloro-1H-indol-3-yl)ethyl)-3′-(trifluoromethyl)biphenyl-2-carboxamide;-   N-(2-(5-chloro-1H-indol-3-yl)ethyl)-2′-(trifluoromethyl)biphenyl-3-carboxamide;-   N-(2-(5-chloro-1H-indol-3-yl)ethyl)-3′-(trifluoromethyl)biphenyl-4-carboxamide;-   N-(2-(5-chloro-1H-indol-3-yl)ethyl)-4′-(trifluoromethyl)biphenyl-2-carboxamide;-   N-(2-(5-chloro-1H-indol-3-yl)ethyl)-4′-(trifluoromethyl)biphenyl-3-carboxamide;-   N-(2-(5-chloro-1H-indol-3-yl)ethyl)-3′-(trifluoromethyl)biphenyl-3-carboxamide;-   N-(2-(5-chloro-1H-indol-3-yl)ethyl)-2′,6′-dimethylbiphenyl-3-carboxamide;-   N-(2-(5-chloro-1H-indol-3-yl)ethyl)-3′,4′-dimethylbiphenyl-2-carboxamide;-   N-(2-(5-chloro-1H-indol-3-yl)ethyl)-3′,4′-dimethylbiphenyl-3-carboxamide;-   N-(2-(5-chloro-1H-indol-3-yl)ethyl)-3′,4′-dimethylbiphenyl-4-carboxamide;-   N-(2-(5-chloro-1H-indol-3-yl)ethyl)-4′-(trifluoromethyl)biphenyl-4-carboxamide;-   N-(2-(5-chloro-1H-indol-3-yl)ethyl)-6-phenylpyridazine-3-carboxamide;-   2-(1H-pyrazol-1-yl)-N-(2-(5-(trifluoromethyl)-1H-indol-3-yl)ethyl)benzamide;-   3-(pyridin-3-yl)-N-(2-(5-(trifluoromethyl)-1H-indol-3-yl)ethyl)benzamide;-   4-(furan-2-yl)-N-(2-(5-(trifluoromethyl)-1H-indol-3-yl)ethyl)benzamide;-   N-(2-(5-cyano-1H-indol-3-yl)ethyl)-3′-fluorobiphenyl-2-carboxamide;-   N-(2-(5-cyano-1H-indol-3-yl)ethyl)-3-(1H-imidazol-5-yl)benzamide;-   N-(2-(5-cyano-1H-indol-3-yl)ethyl)-4-(thiophen-3-yl)benzamide;-   N-(2-(5,6-dichloro-1H-indol-3-yl)ethyl)-2-(1H-pyrazol-1-yl)benzamide;-   N-(2-(5,6-dichloro-1H-indol-3-yl)ethyl)-2′-methylbiphenyl-3-carboxamide;-   N-(2-(5,6-dichloro-1H-indol-3-yl)ethyl)-4-(pyridin-4-yl)benzamide;-   3′-chloro-N-(2-(6-chloro-5-methyl-1H-indol-3-yl)ethyl)biphenyl-2-carboxamide;-   N-(2-(6-chloro-5-methyl-1H-indol-3-yl)ethyl)-2′-cyanobiphenyl-3-carboxamide;-   N-(2-(6-chloro-5-methyl-1H-indol-3-yl)ethyl)-4-(pyridin-2-yl)benzamide;-   N-(2-(5-acetyl-1H-indol-3-yl)ethyl)-2-(oxazol-5-yl)benzamide;-   N-(2-(5-acetyl-1H-indol-3-yl)ethyl)-4′-hydroxybiphenyl-3-carboxamide;-   N-(2-(5-acetyl-1H-indol-3-yl)ethyl)-2′-chlorobiphenyl-4-carboxamide;-   N-(2-(5-chloro-1H-pyrrolo[2,3-b]pyridin-3-yl)ethyl)-2-(oxazol-2-yl)benzamide;-   N-(2-(5-chloro-1H-pyrrolo[2,3-b]pyridin-3-yl)ethyl)-3′-hydroxybiphenyl-3-carboxamide;-   N-(2-(5-chloro-1H-pyrrolo[2,3-b]pyridin-3-yl)ethyl)-4-(thiophen-2-yl)benzamide;-   N-(2-(5-chloro-1H-indol-3-yl)ethyl)-2-(thiophen-3-yl)benzamide;-   N-(2-(5-chloro-1H-indol-3-yl)ethyl)-3-(pyridin-2-yl)benzamide;-   N-(2-(5-chloro-1H-indol-3-yl)ethyl)-4-(oxazol-2-yl)benzamide;-   N-(2-(5-chloro-1H-indol-3-yl)ethyl)-6-(pyridin-3-yl)pyridazine-3-carboxamide;-   N-(2-(6-chloro-5-methyl-1H-indol-3-yl)ethyl)-6-(1-methyl-1H-pyrazol-4-yl)pyridazine-3-carboxamide;-   N-((5-chloro-1H-indol-3-yl)methyl)-3′-fluorobiphenyl-3-carboxamide;-   N-((5-chloro-1H-indol-3-yl)methyl)-4-(oxazol-5-yl)benzamide;-   N-((5-chloro-1H-indol-3-yl)methyl)-6-(pyridin-4-yl)pyridazine-3-carboxamide;-   N-(3-(5-chloro-1H-indol-3-yl)propyl)-2-(1H-pyrazol-1-yl)benzamide;-   N-(3-(5-chloro-1H-indol-3-yl)propyl)-3′-fluorobiphenyl-3-carboxamide;    and-   N-(3-(5-chloro-1H-indol-3-yl)propyl)-4-(oxazol-2-yl)benzamide.

Another aspect of the present invention provides a pharmaceuticalcomposition comprising one or more pharmaceutically acceptableexcipients and a therapeutically effective amount of a compoundaccording to the invention.

Another aspect of the present invention provides the compounds accordingto formula (AA1), (A1), (A2), (A3), (B1), (B2), (B3), (C1), (C2), (C3),(F1), (F2), (F3), (F4), (F5), (G1), (G2), (G3), (G4), (G5), (G6), (G7),(G8), (H1), (H2), (H3), (H4), (I1), (I2), (I3), (I4), (J1), (J2), (J3),(J4), (K1), (K2), (K3), (K4), (L1), (L2), (L3), or (L4) or any subgroupthereof, or all other formulas herein or according to all embodimentsdescribed herein, and isomers (in particular stereo-isomers ortautomers), solvates, hydrates, salts (in particular pharmaceuticallyacceptable salts) or prodrugs thereof, for use as a medicine or amedicament.

In a particular embodiment, the invention provides the compounds for usea medicine for the prevention or treatment of neurodegenerativedisorders, wherein more particularly, the neurodegenerative disorder isselected from Alzheimer's disease, Pick's disease, corticobasaldegeneration, progressive supranuclear palsy, frontotemporal dementia,parkinsonism (linked to chromosome 17, FTDP-17), Parkinson's disease,diffuse Lewy body disease, traumatic brain injury, amyotrophic lateralsclerosis, Niemann-Pick disease, Hallervorden-Spatz syndrome, Downsyndrome, neuroaxonal dystrophy, and multiple system atrophy.

The present invention also provides for the use of the compoundsaccording to formula (AA1), (A1), (A2), (A3), (B1), (B2), (B3), (C1),(C2), (C3), (F1), (F2), (F3), (F4), (F5), (G1), (G2), (G3), (G4), (G5),(G6), (G7), (G8), (H1), (H2), (H3), (H4), (I1), (I2), (I3), (I4), (J1),(J2), (J3), (J4), (K1), (K2), (K3), (K4), (L1), (L2), (L3), or (L4) orany subgroup thereof, or all other formulas herein or according to allembodiments described herein, and isomers (in particular stereo-isomersor tautomers), solvates, hydrates, salts (in particular pharmaceuticallyacceptable salts) or prodrugs thereof, for the manufacture of amedicament for the prevention or treatment of a disorder in an animal,more in particular a mammal or a human.

In a particular embodiment, the invention provides for the use of thecompounds as described herein for the manufacture of a medicament forthe prevention or treatment of a neurodegenerative disorder in ananimal, wherein more particularly, the neurodegenerative disorder isselected from Alzheimer's disease, Pick's disease, corticobasaldegeneration, progressive supranuclear palsy, frontotemporal dementia,parkinsonism (linked to chromosome 17, FTDP-17), Parkinson's disease,diffuse Lewy body disease, traumatic brain injury, amyotrophic lateralsclerosis, Niemann-Pick disease, Hallervorden-Spatz syndrome, Downsyndrome, neuroaxonal dystrophy, and multiple system atrophy.

Another aspect of the invention relates to a method for the preventionor treatment of a disorder in animals, more particularly mammals orhumans, by the administration of an effective amount of one or more suchcompounds according to formula (AA1), (A1), (A2), (A3), (B1), (B2),(B3), (C1), (C2), (C3), (F1), (F2), (F3), (F4), (F5), (G1), (G2), (G3),(G4), (G5), (G6), (G7), (G8), (H1), (H2), (H3), (H4), (I1), (I2), (I3),(I4), (J1), (J2), (J3), (J4), (K1), (K2), (K3), (K4), (L1), (L2), (L3),or (L4) or any subgroup thereof, or all other formulas herein oraccording to all embodiments described herein, and isomers (inparticular stereo-isomers or tautomers), solvates, hydrates, salts (inparticular pharmaceutically acceptable salts) or prodrugs thereof to apatient in need thereof. In a particular embodiment, said disorder is aneurodegenerative disorder, wherein more particularly, theneurodegenerative disorder is selected from Alzheimer's disease, Pick'sdisease, corticobasal degeneration, progressive supranuclear palsy,frontotemporal dementia, parkinsonism (linked to chromosome 17,FTDP-17), Parkinson's disease, diffuse Lewy body disease, traumaticbrain injury, amyotrophic lateral sclerosis, Niemann-Pick disease,Hallervorden-Spatz syndrome, Down syndrome, neuroaxonal dystrophy, andmultiple system atrophy.

Another aspect of the present invention provides a pharmaceuticalcomposition comprising one or more pharmaceutically acceptable carriersor excipients and a therapeutically effective amount of a compoundaccording to formula (AA1), (A1), (A2), (A3), (B1), (B2), (B3), (C1),(C2), (C3), (F1), (F2), (F3), (F4), (F5), (G1), (G2), (G3), (G4), (G5),(G6), (G7), (G8), (H1), (H2), (H3), (H4), (I1), (I2), (I3), (I4), (J1),(J2), (J3), (J4), (K1), (K2), (K3), (K4), (L1), (L2), (L3), or (L4) orany subgroup thereof, or all other formulas herein or according to allembodiments described herein, and isomers (in particular stereo-isomersor tautomers), solvates, hydrates, salts (in particular pharmaceuticallyacceptable salts) or prodrugs thereof.

In a particular embodiment, the present invention relates topharmaceutical compositions comprising the compounds of the inventionaccording to formulae, embodiments and claims herein in admixture withat least a pharmaceutically acceptable carrier, the active compoundspreferably being in a concentration range of about 0.1 to 100% byweight.

The invention further relates to the use of a composition comprising (a)one or more compounds of the invention (of formulae, embodiments andclaims herein), and (b) one or more drugs known for the (symptomatic)prevention or treatment of neurodegenerative disorders.

Yet another aspect of the invention provides a method for thepreparation of the compounds of the invention which comprises thefollowing steps (with the knowledge that where indole is described, thesame counts for the corresponding heterocycles as described herein i.e.aza-indole):

-   -   reacting a substituted or unsubstituted        (1H-indol-3-yl)methanamine, 2-(1H-indol-3-yl)ethanamine or        3-(1H-indol-3-yl)propan-1-amine with a correctly substituted six        membered ring derivative bearing an acid halide function in a        polar aprotic solvent in the presence of a strong base at a        temperature between −10° C. to 100° C.;    -   reacting a substituted or unsubstituted        (1H-indol-3-yl)methanamine, 2-(1H-indol-3-yl)ethanamine or        3-(1H-indol-3-yl)propan-1-amine with a correctly substituted six        membered ring derivative bearing one carboxylic acid function in        a polar aprotic solvent in the presence of a peptide bond        formation coupling agent at a temperature between 0° C. to 50°        C.;    -   optionally reacting the compound obtained in the previous step,        wherein the six membered ring bears a leaving group (LG), with        suitable nucleophiles (e.g. amines, alcohols) and in the        presence of a strong base or with derivatives such as boronic        acids, stannanes or organozinc derivatives in the presence of a        palladium or cupper catalyst.

Also the intermediates used in the preparation methods described hereinare aspects of the present invention.

Particular embodiments of the inventions are also described in theclaims and relate to especially useful subtypes of the compounds of theinvention. In particular embodiments, the terms alkyl, alkenyl oralkynyl can be restricted to refer to their cyclic or linear subgroups(such as the linear alkyl or cycloalkyl for alkyl).

More generally, the invention relates to the compounds of formula andclaims herein being useful as agents having biological activity or asdiagnostic agents. Any of the uses mentioned with respect to the presentinvention may be restricted to a non-medical use, a non-therapeutic use,a non-diagnostic use, or exclusively an in vitro use, or a use relatedto cells remote from an animal.

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1 shows the sensitivity of a TAU(301) expressing neuroblastoma cellline to retinoic acid-instigated differentiation.

FIG. 2 shows the sensitivity of an α-synuclein expressing neuroblastomacell line to paraquat.

DETAILED DESCRIPTION OF THE INVENTION

As used in the foregoing and hereinafter, the following definitionsapply unless otherwise noted.

The terminology “which optionally includes one or more heteroatoms, saidheteroatoms being selected from the atoms consisting of O, S, and N” asused herein, refers to a group where one or more carbon atoms arereplaced by an oxygen, nitrogen or sulphur atom and thus includes,depending on the group to which is referred, heteroalkyl, heteroalkenyl,heteroalkynyl, heteroalkylene, heteroalkenylene, heteroalkynylene,cycloheteroalkyl, cycloheteroalkenyl, cycloheteroalkynyl, heteroaryl,arylheteroalkyl(ene), heteroarylalkyl(ene), heteroarylheteroalkyl(ene),arylheteroalkenyl(ene), heteroarylalkenyl(ene),heteroarylheteroalkenyl(ene), heteroarylheteroalkenyl(ene),arylheteroalkynyl(ene), heteroarylalkynyl(ene),heteroarylheteroalkynyl(ene), among others. In other words, this termmeans that —CH₃ can be replaced by —NH₂; —CH₂— by —NH—, —O— or —S—; a—CH═ by —N═; and ≡CH by ≡N. This term therefore comprises, depending onthe group to which is referred, as an example alkoxy, alkenyloxy,alkynyloxy, alkyl-O-alkylene, alkenyl-O-alkylene, arylalkoxy, benzyloxy,heterocycle-heteroalkyl, heterocycle-alkoxy, among others. As anexample, the terminology “alkyl which optionally includes one or moreheteroatoms, said heteroatoms being selected from the atoms consistingof O, S, and N” therefore refers to heteroalkyl, meaning an alkyl whichcomprises one or more heteroatoms in the hydrocarbon chain, whereas theheteroatoms may be positioned at the beginning of the hydrocarbon chain,in the hydrocarbon chain or at the end of the hydrocarbon chain.Examples of heteroalkyl include methoxy, methylthio, ethoxy, propoxy,CH₃—O—CH₂—, CH₃—S—CH₂—, CH₃—CH₂—O—CH₂—, CH₃—NH—, (CH₃)₂—N—,(CH₃)₂—CH₂—NH—CH₂—CH₂—, among many other examples. As an example, theterminology “arylalkylene which optionally includes one or moreheteroatoms in the alkylene chain, said heteroatoms being selected fromthe atoms consisting of O, S, and N” therefore refers toarylheteroalkylene, meaning an arylalkylene which comprises one or moreheteroatoms in the hydrocarbon chain, whereas the heteroatoms may bepositioned at the beginning of the hydrocarbon chain, in the hydrocarbonchain or at the end of the hydrocarbon chain. “Arylheteroalkylene” thusincludes aryloxy, arylalkoxy, aryl-alkyl-NH— and the like and examplesare phenyloxy, benzyloxy, aryl-CH₂—S—CH₂—, aryl-CH₂—O—CH₂—, aryl-NH—CH₂—among many other examples. The same counts for “heteroalkenylene”,“heteroalkynylene”, and other terms used herein when referred to “whichoptionally includes one or more heteroatoms, said heteroatoms beingselected from the atoms consisting of O, S, and N”.

The terminology regarding a chemical group “wherein optionally two ormore hydrogen atoms on a carbon atom or heteroatom of said group can betaken together to form a C═O, C═S, N═O, N═S, S═O or S(O)₂” as usedherein, refers to a group where two or more hydrogen atoms on a carbonatom or heteroatom of said group are taken together to form C═O, C═S,N═O, N═S, S═O or S(O)₂. In other words, the expression means that acarbon atom or heteroatom of said group can be oxidized to form a C═O,C═S, N═O, N═S, S═O or S(O)₂. As an example, the terminology refers to“an alkyl wherein optionally two or more hydrogen atoms on a carbon atomor heteroatom of said alkyl can be taken together to form a C═O, C═S,N═O, N═S, S═O or S(O)₂”, includes among other examples CH₃—C(O)—CH₂—,CH₃—C(O)—, CH₃—C(S)—CH₂— and (CH₃)₂—CH₂—C(O)—CH₂—CH₂—. As anotherexample, as used herein and unless otherwise stated, the expression “twoor more hydrogen atoms on a carbon atom or heteroatom of saidheterocycle can be taken together to form a C═O, C═S, N═O, N═S, S═O orS(O)₂” means that a carbon atom or heteroatom of the ring can beoxidized to form a C═O, C═S, N═O, N═S, S═O or S(O)₂. The combination fora group “which optionally includes one or more heteroatoms, saidheteroatoms being selected from the atoms consisting of O, S, and N” and“wherein optionally two or more hydrogen atoms on a carbon atom orheteroatom of said group can be taken together to form a C═O, C═S, N═O,N═S, S═O or S(O)₂” can combine the two aspects described herein aboveand includes, if the group referred to is alkyl, among other examplesCH₃—COO—, CH₃—COO—CH₂—, CH₃—NH—CO—, CH₃—NH—CO—OH₂—, CH₃—NH—CS—CH₂—,CH₃—NH—CS—NH—CH₂—, CH₃—NH—S(O)₂— and CH₃—NH—S(O)₂—NH—CH₂—.

The term “leaving group” as used herein means a chemical group which issusceptible to be displaced by a nucleophile or cleaved off orhydrolysed in basic or acidic conditions. In a particular embodiment, aleaving group is selected from a halogen atom (e.g., Cl, Br, I) or asulfonate (e.g., mesylate, tosylate, triflate).

The term “alkyl” as used herein means C₁-C₁₈ normal, secondary, ortertiary, linear or cyclic, branched or straight hydrocarbon with nosite of unsaturation. Examples are methyl, ethyl, 1-propyl, 2-propyl,1-butyl, 2-methyl-1-propyl(i-Bu), 2-butyl(s-Bu) 2-methyl-2-propyl(t-Bu),1-pentyl(n-pentyl), 2-pentyl, 3-pentyl, 2-methyl-2-butyl,3-methyl-2-butyl, 3-methyl-1-butyl, 2-methyl-1-butyl, 1-hexyl, 2-hexyl,3-hexyl, 2-methyl-2-pentyl, 3-methyl-2-pentyl, 4-methyl-2-pentyl,3-methyl-3-pentyl, 2-methyl-3-pentyl, 2,3-dimethyl-2-butyl,3,3-dimethyl-2-butyl, cyclopropyl, cyclobutyl, cyclopentyl andcyclohexyl. In a particular embodiment, the term alkyl refers to C₁₋₁₂hydrocarbons, yet more in particular to C₁₋₆ hydrocarbons, also termedas C₁₋₆alkyl, as further defined herein above.

The term “linear alkyl” as used herein means C₁-C₁₈ normal, secondary,or tertiary, linear, branched or straight, hydrocarbon with no site ofunsaturation. Examples are methyl, ethyl, 1-propyl, 2-propyl, 1-butyl,2-methyl-1-propyl(i-Bu), 2-butyl(s-Bu) 2-methyl-2-propyl(t-Bu),1-pentyl(n-pentyl), 2-pentyl, 3-pentyl, 2-methyl-2-butyl,3-methyl-2-butyl, 3-methyl-1-butyl, 2-methyl-1-butyl, 1-hexyl, 2-hexyl,3-hexyl, 2-methyl-2-pentyl, 3-methyl-2-pentyl, 4-methyl-2-pentyl,3-methyl-3-pentyl, 2-methyl-3-pentyl, 2,3-dimethyl-2-butyl and3,3-dimethyl-2-butyl.

As used herein and unless otherwise stated, the term “cycloalkyl” meansa monocyclic saturated hydrocarbon monovalent radical having from 3 to10 carbon atoms, such as for instance cyclopropyl, cyclobutyl,cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl and the like, or aC₇₋₁₀ polycyclic saturated hydrocarbon monovalent radical having from 7to 10 carbon atoms such as, for instance, norbornyl, fenchyl,trimethyltricycloheptyl or adamantyl. In a particular embodiment, theterm cycloalkyl refers to C₃₋₈cycloalkyl, which is a generic term forcyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, andcyclooctyl.

The term “alkenyl” as used herein is C₂-C₁₈ normal, secondary ortertiary, linear or cyclic, branched or straight hydrocarbon with atleast one site (usually 1 to 3, preferably 1) of unsaturation, namely acarbon-carbon, sp2 double bond. Examples include, but are not limitedto: ethylene or vinyl (—CH≡CH₂), allyl (—CH₂CH═CH₂), cyclopentenyl(—C₅H₇), cyclohexenyl (—C₆H₉) and 5-hexenyl (—CH₂CH₂CH₂CH₂CH═CH₂). Thedouble bond may be in the cis or trans configuration. In a particularembodiment, the term alkenyl refers to C₂₋₁₂ hydrocarbons, yet more inparticular to C₂₋₆ hydrocarbons, also termed as C₂₋₆alkenyl, as furtherdefined herein above.

The term “linear alkenyl” as used herein refers to C₂-C₁₈ normal,secondary or tertiary, linear, branched or straight hydrocarbon with atleast one site (usually 1 to 3, preferably 1) of unsaturation, namely acarbon-carbon, sp2 double bond. Examples include, but are not limitedto: ethylene or vinyl (—CH═CH₂), allyl (—CH₂CH═CH₂) and 5-hexenyl(—CH₂CH₂CH₂CH₂CH═CH₂). The double bond may be in the cis or transconfiguration.

The term “cycloalkenyl” as used herein refers to C₄-C₁₈ normal,secondary or tertiary, cyclic hydrocarbon with at least one site(usually 1 to 3, preferably 1) of unsaturation, namely a carbon-carbon,sp2 double bond. Examples include, but are not limited to: cyclopentenyl(—C₅H₇) and cyclohexenyl (—C₆H₉). The double bond may be in the cis ortrans configuration.

The term “alkynyl” as used herein refers to C₂-C₁₈ normal, secondary,tertiary, linear or cyclic, branched or straight hydrocarbon with atleast one site (usually 1 to 3, preferably 1) of unsaturation, namely acarbon-carbon, sp triple bond. Examples include, but are not limited to:acetylenic (—C≡CH) and propargyl (—CH₂C≡CH). In a particular embodiment,the term alkenyl refers to C₂₋₁₂ hydrocarbons, yet more in particular toC₂₋₆ hydrocarbons, also termed as C₂₋₆alkynyl, as further defined hereinabove.

The term “linear alkynyl” as used herein refers to C₂-C₁₈ normal,secondary, tertiary, linear, branched or straight hydrocarbon with atleast one site (usually 1 to 3, preferably 1) of unsaturation, namely acarbon-carbon, sp triple bond. Examples include, but are not limited to:acetylenic (—C≡CH) and propargyl (—CH₂C≡CH).

The term “cycloalkynyl” as used herein refers to C₆-C₁₈ normal,secondary, tertiary, cyclic hydrocarbon with at least one site (usually1 to 3, preferably 1) of unsaturation, namely a carbon-carbon, sp triplebond. Examples include, but are not limited to: cyclohex-1-yne andethylene-cyclohex-1-yne.

The terms “alkylene” as used herein each refer to a saturated, branchedor straight chain hydrocarbon radical of 1-18 carbon atoms (more inparticular 1-12 or 1-6 carbon atoms), and having two monovalent radicalcenters derived by the removal of two hydrogen atoms from the same ortwo different carbon atoms of a parent alkane. Typical alkylene radicalsinclude, but are not limited to: methylene (—CH₂—) 1,2-ethylene(—CH₂CH₂—), 1,2-propylene, 1,3-propylene (—CH₂CH₂CH₂—), 1,4-butylene(—CH₂CH₂CH₂CH₂—), 1,3-butylene, 1,2-butylene, and the like.

The term “aryl” as used herein means a aromatic hydrocarbon radical of6-20 carbon atoms derived by the removal of hydrogen from a carbon atomof a parent aromatic ring system. Typical aryl groups include, but arenot limited to 1 ring, or 2 or 3 rings fused together, radicals derivedfrom benzene, naphthalene, anthracene, biphenyl, and the like. In aparticular embodiment, the term “parent aromatic ring system” means amonocyclic aromatic ring system or a bi- or tricyclic ring system ofwhich at least one ring is aromatic. Therefore, in this embodiment,typical aryl groups include, but are not limited to 1 ring, or 2 or 3rings fused together, radicals derived from benzene, naphthalene,anthracene, biphenyl, 2,3-dihydro-1H-indenyl,5,6,7,8-tetrahydronaphthalenyl, 1,2,6,7,8,8a-hexahydroacenaphthylenyl,1,2-dihydroacenaphthylenyl, and the like.

“Arylalkylene” as used herein refers to an alkyl radical in which one ofthe hydrogen atoms bonded to a carbon atom, typically a terminal or sp3carbon atom, is replaced with an aryl radical. Typical arylalkylenegroups include, but are not limited to, benzyl, 2-phenylethan-1-yl,2-phenylethen-1-yl, naphthylmethyl, 2-naphthylethan-1-yl,2-naphthylethen-1-yl, naphthobenzyl, 2-naphthophenylethan-1-yl and thelike. The arylalkylene group comprises 6 to 20 carbon atoms, e.g. thealkylene moiety of the arylalkylene group is 1 to 6 carbon atoms and thearyl moiety is 5 to 14 carbon atoms.

“Arylalkenylene” as used herein refers to an alkenylene radical in whichone of the hydrogen atoms bonded to a carbon atom, is replaced with anaryl radical. The arylalkenylene group comprises 6 to 20 carbon atoms,e.g. the alkenylene moiety of the arylalkenylene group is 2 to 6 carbonatoms and the aryl moiety is 5 to 14 carbon atoms.

“Arylalkynylene” as used herein refers to an alkynyl radical in whichone of the hydrogen atoms bonded to a carbon atom, is replaced with anaryl radical. The arylalkynylene group comprises 6 to 20 carbon atoms,e.g. the alkynylene moiety of the arylalkynylene group is 2 to 6 carbonatoms and the aryl moiety is 5 to 14 carbon atoms.

The term “heterocycle” as used herein means a saturated, unsaturated oraromatic ring system including at least one N, O, S, or P. Heterocyclethus include heteroaryl groups. Heterocycle as used herein includes byway of example and not limitation these heterocycles described inPaquette, Leo A. “Principles of Modern Heterocyclic Chemistry” (W. A.Benjamin, New York, 1968), particularly Chapters 1, 3, 4, 6, 7, and 9;“The Chemistry of Heterocyclic Compounds, A series of Monographs” (JohnWiley & Sons, New York, 1950 to present), in particular Volumes 13, 14,16, 19, and 28; Katritzky, Alan R., Rees, C. W. and Scriven, E.“Comprehensive Heterocyclic Chemistry” (Pergamon Press, 1996); and J.Am. Chem. Soc. (1960) 82:5566. In a particular embodiment, the termmeans pyridyl, dihydroypyridyl, tetrahydropyridyl(piperidyl), thiazolyl,tetrahydrothiophenyl, sulfur oxidized tetrahydrothiophenyl, furanyl,thienyl, pyrrolyl, pyrazolyl, imidazolyl, tetrazolyl, benzofuranyl,thianaphthalenyl, indolyl, indolenyl, quinolinyl, isoquinolinyl,benzimidazolyl, piperidinyl, 4-piperidonyl, pyrrolidinyl,2-pyrrolidonyl, pyrrolinyl, tetrahydrofuranyl, bis-tetrahydrofuranyl,tetrahydropyranyl, bis-tetrahydropyranyl, tetrahydroquinolinyl,tetrahydroisoquinolinyl, decahydroquinolinyl, octahydroisoquinolinyl,azocinyl, triazinyl, 6H-1,2,5-thiadiazinyl, 2H,6H-1,5,2-dithiazinyl,thianthrenyl, pyranyl, isobenzofuranyl, chromenyl, xanthenyl,phenoxathinyl, 2H-pyrrolyl, isothiazolyl, isoxazolyl, pyrazinyl,pyridazinyl, indolizinyl, isoindolyl, 3H-indolyl, 1H-indazoly, purinyl,4H-quinolizinyl, phthalazinyl, naphthyridinyl, quinoxalinyl,quinazolinyl, cinnolinyl, pteridinyl, 4aH-carbazolyl, carbazolyl,fl-carbolinyl, phenanthridinyl, acridinyl, pyrimidinyl, phenanthrolinyl,phenazinyl, phenothiazinyl, furazanyl, phenoxazinyl, isochromanyl,chromanyl, imidazolidinyl, imidazolinyl, pyrazolidinyl, pyrazolinyl,piperazinyl, indolinyl, isoindolinyl, quinuclidinyl, morpholinyl,oxazolidinyl, benzotriazolyl, benzisoxazolyl, oxindolyl, benzoxazolinyl,benzothienyl, benzothiazolyl and isatinoyl.

“Heterocycle-alkylene” as used herein refers to an alkyl radical inwhich one of the hydrogen atoms bonded to a carbon atom, typically aterminal or sp3 carbon atom, is replaced with a heterocycle radical. Anexample of a heterocycle-alkylene group is 2-pyridyl-methylene. Theheterocycle-alkylene group comprises 6 to 20 carbon atoms, e.g. thealkylene moiety of the heterocycle-alkyl group is 1 to 6 carbon atomsand the heterocycle moiety is 5 to 14 carbon atoms.

“Heterocycle-alkenylene” as used herein refers to an alkenyl radical inwhich one of the hydrogen atoms bonded to a carbon atom, is replacedwith an heterocycle radical. The heterocycle-alkenylene group comprises6 to 20 carbon atoms, e.g. the alkenylene moiety of theheterocycle-alkenylene group is 2 to 6 carbon atoms and the heterocyclemoiety is 5 to 14 carbon atoms.

“Heterocycle-alkynylene” as used herein refers to an alkynylene radicalin which one of the hydrogen atoms bonded to a carbon atom, is replacedwith a heterocycle radical. The heterocycle-alkynylene group comprises 6to 20 carbon atoms, e.g. the alkynylene moiety of theheterocycle-alkynylene group is 2 to 6 carbon atoms and the heterocyclemoiety is 5 to 14 carbon atoms.

“Heteroaryl” means an aromatic ring system including at least one N, O,S, or P. Examples of heteroaryl include but are not limited to pyridyl,dihydropyridyl, pyridazinyl, pyrimidinyl, pyrazinyl, s-triazinyl,oxazolyl, imidazolyl, thiazolyl, isoxazolyl, pyrazolyl, isothiazolyl,furanyl, thiofuranyl, thienyl, and pyrrolyl.

“Heteroaryl-alkylene” as used herein refers to an alkyl radical in whichone of the hydrogen atoms bonded to a carbon atom, typically a terminalor sp3 carbon atom, is replaced with a heterocycle radical. An exampleof a heteroaryl-alkylene group is 2-pyridyl-methylene. Theheteroaryl-alkylene group comprises 6 to 20 carbon atoms, e.g. thealkylene moiety of the heteroaryl-alkylene group is 1 to 6 carbon atomsand the heteroaryl moiety is 5 to 14 carbon atoms.

“Heteroaryl-alkenylene” as used herein refers to an alkenyl radical inwhich one of the hydrogen atoms bonded to a carbon atom, is replacedwith an heteroaryl radical. The heteroaryl-alkenylene group comprises 6to 20 carbon atoms, e.g. the alkenylene moiety of theheteroaryl-alkenylene group is 2 to 6 carbon atoms and the heteroarylmoiety is 5 to 14 carbon atoms.

“Heteroaryl-alkynylene” as used herein refers to an alkynyl radical inwhich one of the hydrogen atoms bonded to a carbon atom, is replacedwith a heteroaryl radical. The heteroaryl-alkynylene group comprises 6to 20 carbon atoms, e.g. the alkynylene moiety of theheteroaryl-alkynylene group is 2 to 6 carbon atoms and the heteroarylmoiety is 5 to 14 carbon atoms.

By way of example, carbon bonded heterocyclic rings are bonded atposition 2, 3, 4, 5, or 6 of a pyridine, position 3, 4, 5, or 6 of apyridazine, position 2, 4, 5, or 6 of a pyrimidine, position 2, 3, 5, or6 of a pyrazine, position 2, 3, 4, or 5 of a furan, tetrahydrofuran,thiofuran, thiophene, pyrrole or tetrahydropyrrole, position 2, 4, or 5of an oxazole, imidazole or thiazole, position 3, 4, or 5 of anisoxazole, pyrazole, or isothiazole, position 2 or 3 of an aziridine,position 2, 3, or 4 of an azetidine, position 2, 3, 4, 5, 6, 7, or 8 ofa quinoline or position 1, 3, 4, 5, 6, 7, or 8 of an isoquinoline. Stillmore typically, carbon bonded heterocycles include 2-pyridyl, 3-pyridyl,4-pyridyl, 5-pyridyl, 6-pyridyl, 3-pyridazinyl, 4-pyridazinyl,5-pyridazinyl, 6-pyridazinyl, 2-pyrimidinyl, 4-pyrimidinyl,5-pyrimidinyl, 6-pyrimidinyl, 2-pyrazinyl, 3-pyrazinyl, 5-pyrazinyl,6-pyrazinyl, 2-thiazolyl, 4-thiazolyl, or 5-thiazolyl.

By way of example, nitrogen bonded heterocyclic rings are bonded atposition 1 of an aziridine, azetidine, pyrrole, pyrrolidine,2-pyrroline, 3-pyrroline, imidazole, imidazolidine, 2-imidazoline,3-imidazoline, pyrazole, pyrazoline, 2-pyrazoline, 3-pyrazoline,piperidine, piperazine, indole, indoline, 1H-indazole, position 2 of aisoindole, or isoindoline, position 4 of a morpholine, and position 9 ofa carbazole, or β-carboline. Still more typically, nitrogen bondedheterocycles include 1-aziridyl, 1-azetedyl, 1-pyrrolyl, 1-imidazolyl,1-pyrazolyl, and 1-piperidinyl.

As used herein and unless otherwise stated, the terms “alkoxy”,“cycloalkoxy”, “aryloxy”, “arylalkyloxy”, “oxyheterocycle ring”,“thio-alkyl”, “thio-cycloalkyl”, “arylthio”, “arylalkylthio” and“thioheterocycle” refer to substituents wherein an alkyl radical,respectively a cycloalkyl, aryl, arylalkyl or heterocycle radical (eachof them such as defined herein), are attached to an oxygen atom or asulfur atom through a single bond, such as but not limited to methoxy,ethoxy, propoxy, butoxy, thioethyl, thiomethyl, phenyloxy, benzyloxy,mercaptobenzyl and the like. The same definitions will apply for alkenyland alkynyl radicals in stead of alkyl.

As used herein and unless otherwise stated, the term halogen means anyatom selected from the group consisting of fluorine, chlorine, bromineand iodine.

Whenever the term “substituted” is used in the present invention, andunless otherwise stated, it is meant to indicate that one or morehydrogens on the atom, or group indicated in the expression using“substituted” is replaced with one or more group each independentlyselected from halogen; alkyl; alkenyl; alkynyl; —OH; —OR¹⁰; —SH; —SR¹⁰;—S(O)R¹¹; —S(O)₂R¹¹; —SO₂NR¹²R¹³; trifluoromethyl; trifluoromethoxy;nitro; —NHC(O)R¹⁰; —NHS(O)₂R¹⁰; —NHC(O)NR¹²R¹³; —NR¹⁰C(O)R¹⁰;—NR¹⁰S(O)₂R¹⁰; —NR¹⁰C(O)NR¹²R¹³; —NR¹²R¹³; -cyano; —COOH; —COOR¹⁰;—C(O)NR¹²R¹³; —C(O)R¹¹; wherein R¹⁰, R¹¹, R¹², R¹³ have the same meaningas that defined herein.

Any substituent designation that is found in more than one site in acompound of this invention shall be independently selected.

Substituents optionally are designated with or without bonds. Regardlessof bond indications, if a substituent is polyvalent (based on itsposition in the structure referred to), then any and all possibleorientations of the substituent are intended.

As used herein and unless otherwise stated, the term “stereoisomer”refers to all possible different isomeric as well as conformationalforms which the compounds of structural formula herein may possess, inparticular all possible stereochemically and conformationally isomericforms, all diastereomers, enantiomers and/or conformers of the basicmolecular structure. Some compounds of the present invention may existin different tautomeric forms, all of the latter being included withinthe scope of the present invention.

As used herein and unless otherwise stated, the term “enantiomer” meanseach individual optically active form of a compound of the invention,having an optical purity or enantiomeric excess (as determined bymethods standard in the art) of at least 80% (i.e. at least 90% of oneenantiomer and at most 10% of the other enantiomer), preferably at least90% and more preferably at least 98%.

Pure stereoisomeric forms of the compounds and intermediates of thisinvention may be obtained by the application of art-known procedures.For instance, enantiomers may be separated from each other by theselective crystallization of their diastereomeric salts with opticallyactive acids or bases. Examples thereof are tartaric acid,dibenzoyltartaric acid, ditoluoyltartaric acid and camphorsulfonic acid.Alternatively, enantiomers may be separated by chromatographictechniques using chiral stationary phases. Said pure stereochemicallyisomeric forms may also be derived from the corresponding purestereochemically isomeric forms of the appropriate starting materials,provided that the reaction occur stereospecifically. Preferably, if aspecific stereoisomer is desired, said compound will be synthesized bystereospecific methods of preparation. These methods will advantageouslyemploy enantiomerically pure starting materials.

The diastereomeric racemates of the compounds of the invention can beobtained separately by conventional methods. Appropriate physicalseparation methods that may advantageously be employed are, for example,selective crystallization and chromatography, e.g. columnchromatography.

For therapeutic use, salts of the compounds of the invention are thosewherein the counter-ion is pharmaceutically acceptable, which salts canbe referred to as pharmaceutically acceptable acid and base additionsalts. However, salts of acids and bases that are non-pharmaceuticallyacceptable may also find use, for example, in the preparation orpurification of a pharmaceutically acceptable compound. All salts,whether pharmaceutically acceptable or not, are included within theambit of the present invention.

The pharmaceutically acceptable acid and base addition salts asmentioned hereinabove are meant to comprise the therapeutically activenon-toxic acid and base addition salt forms that the compounds are ableto form. The pharmaceutically acceptable acid addition salts canconveniently be obtained by treating the base form with such appropriateacid in an anion form. Appropriate anions comprise, for example,acetate, benzenesulfonate, benzoate, bicarbonate, bitartrate, bromide,calcium edetate, camsyiate, carbonate, chloride, citrate,dihydrochloride, edetate, edisylate, estolate, esylate, fumarate,gluceptate, gluconate, glutamate, glycollylarsanilate, hexylresorcinate,hydrabamine, hydrobromide, hydrochloride, hydroxynaphthoate, iodide,isethionate, lactate, lactobionate, malate, maleate, mandelate,mesylate, methylbromide, methylnitrate, methylsulfate, mucate,napsylate, nitrate, pamoate (embonate), pantothenate,phosphate/diphosphate, polygalacturonate, salicylate, stearate,subacetate, succinate, sulfate, tannate, tartrate, teoclate,triethiodide, and the like. Conversely said salt forms can be convertedby treatment with an appropriate base into the free base form.

The compounds of the invention containing an acidic proton may also beconverted into their non-toxic metal or amine addition salt forms bytreatment with appropriate organic and inorganic bases in a cation form.Appropriate basic salts comprise those formed with organic cations suchas benzathine, chloroprocaine, choline, diethanolamine, ethylenediamine,meglumine, procaine, and the like; and those formed with metalliccations such as aluminum, calcium, lithium, magnesium, potassium,sodium, zinc, and the like. Conversely said salt forms can be convertedby treatment with an appropriate acid into the free form.

As used herein and unless otherwise stated, the term “solvate” includesany combination which may be formed by a derivative of this inventionwith a suitable inorganic solvent (e.g. hydrates) or organic solvent,such as but not limited to alcohols, ketones, esters, ethers, nitrilesand the like.

A first aspect of the present invention therefore provides compoundsaccording to formula (AA1) or (A1),

wherein E, R¹, R², R³, R⁴, R⁵, R⁶, R⁸, Y¹, Y², Y³, Y⁴, Y⁵, X¹, X², X³,X⁴, X⁵, B, m and n have the same meaning as that defined herein(including in the summary of the invention, the formulas and embodimentsthereof).

According to an embodiment, the present invention provides compounds ofFormula (AA1), (A1), (A2), (A3), (B1), (B2), (B3), (C1), (C2), (C3),(F1), (F2), (F3), (F4), (F5), (G1), (G2), (G3), (G4), (G5), (G6), (G7),(G8), (H1), (H2), (H3), (H4), (I1), (I2), (I3), (I4), (J1), (J2), (J3),or (J4) or any subgroup thereof, wherein E is CR³; or N; preferably E isCR³,

-   each R¹, R⁴ and R⁶ is independently selected from hydrogen; halogen;    —OH; —OR¹⁰; —SH; —SR¹⁰; —S(O)R¹¹; —S(O)₂R¹¹; —SO₂NR¹²R¹³;    trifluoromethyl; trifluoromethoxy; nitro; —NHC(O)R¹⁰; —NHS(O)₂R¹⁰;    —NHC(O)NR¹²R¹³; —NR¹⁰C(O)R¹⁰; —NR¹⁰S(O)₂R¹⁰; —NR¹⁰C(O)NR¹²R¹³;    —NR¹²R¹³; -cyano; —COOH; —COOR¹⁰; —C(O)NR¹²R¹³; —C(O)R¹¹; C₁₋₆alkyl;    C₂₋₆alkenyl; C₂₋₆alkynyl; C₆₋₁₀aryl; heterocycle;    C₆₋₁₀arylC₁₋₆alkylene; C₆₋₁₀arylC₂₋₆alkenylene;    C₆₋₁₀arylC₂₋₆alkynylene; heterocycle-C₁₋₆alkylene;    heterocycle-C₂₋₆alkenylene; and heterocycle-C₂₋₆alkynylene;    preferably each R¹, R⁴ and R⁶ is independently selected from    hydrogen; halogen; —OH; —OR¹⁰; —SH; trifluoromethyl;    trifluoromethoxy; nitro; —NR¹²R¹³; -cyano; —COOH; —COOR¹⁰;    C₁₋₆alkyl; C₆₋₁₀aryl; heterocycle; C₆₋₁₀arylC₁₋₆alkylene;    heterocycle-C₁₋₆alkylene; preferably each R¹, R⁴ and R⁶ is    independently selected from hydrogen; halogen; —OH; —OC₁₋₄alkyl;    trifluoromethyl; trifluoromethoxy; -cyano; C₁₋₄alkyl; C₆aryl;    C₆arylC₁₋₆alkylene; preferably each R¹, R⁴ and R⁶ is independently    selected from hydrogen; halogen; —OH; methoxy; trifluoromethyl;    trifluoromethoxy; -cyano; C₁₋₄alkyl; C₆aryl; preferably each R¹, R⁴    and R⁶ is independently selected from hydrogen; halogen; —OH;    trifluoromethyl; C₁₋₂alkyl; preferably each R¹, R⁴ and R⁶ is    independently selected from hydrogen; fluoro; or chloro; preferably    each R¹, R⁴ and R⁶ is independently hydrogen;-   R³ is selected from hydrogen; halogen; —OH; —OR¹⁰; —SH; —SR¹⁰;    —S(O)R¹¹; —S(O)₂R¹¹; —SO₂NR¹²R¹³; trifluoromethyl; trifluoromethoxy;    nitro; —NHC(O)R¹⁰; —NHS(O)₂R¹⁰; —NHC(O)NR¹²R¹³; —NR¹⁰C(O)R¹⁰;    —NR¹⁰S(O)₂R¹⁰; —NR¹⁰C(O)NR¹²R¹³; —NR¹²R¹³; -cyano; —COOH; —COOR¹⁰;    —C(O)NR¹²R¹³; —C(O)R¹¹; C₁₋₆alkyl; C₂₋₆alkenyl; C₂₋₆alkynyl;    C₆₋₁₀aryl; heterocycle; C₆₋₁₀arylC₁₋₆alkylene;    C₆₋₁₀arylC₂₋₆alkenylene; C₆₋₁₀arylC₂₋₆alkynylene;    heterocycle-C₁₋₆alkylene; heterocycle-C₂₋₆alkenylene; and    heterocycle-C₂₋₆alkynylene; preferably R³ is selected from hydrogen;    halogen; —OH; —OR¹⁰; —SH; trifluoromethyl; trifluoromethoxy; nitro;    —NR¹²R¹³; -cyano; —COOH; —COOR¹⁰; C₁₋₆alkyl; C₆₋₁₀aryl; heterocycle;    C₆₋₁₀arylC₁₋₆alkylene; heterocycle-C₁₋₆alkylene; preferably R³ is    selected from hydrogen; halogen; —OH; trifluoromethyl;    trifluoromethoxy; -cyano; C₁₋₄alkyl; C₆aryl; C₆arylC₁₋₆alkylene;    preferably R³ is selected from hydrogen; halogen; —OH; methoxy;    trifluoromethyl; trifluoromethoxy; -cyano; C₁₋₄alkyl; C₆aryl;    preferably R³ is selected from hydrogen; halogen; —OH;    trifluoromethyl; C₁₋₂alkyl; preferably R³ is selected from hydrogen;    fluoro; or chloro; preferably R³ is hydrogen;-   R² is selected from hydrogen; C₁₋₆alkyl; C₂₋₆alkenyl; and    C₂₋₆alkynyl; preferably R² is selected from hydrogen; or C₁₋₆alkyl;    preferably R² is selected from hydrogen; or C₁₋₂alkyl; preferably R²    is hydrogen;-   R⁵ is selected from halogen; —OH; —OR¹⁰; —SH; —SR¹⁰; —S(O)R¹¹;    —S(O)₂R¹¹; —SO₂NR¹²R¹³; trifluoromethyl; trifluoromethoxy; nitro;    —NHC(O)R¹⁰; —NHS(O)₂R¹⁰; —NHC(O)NR¹²R¹³; —NR¹⁰C(O)R¹⁰;    —NR¹⁰S(O)₂R¹⁰; —NR¹⁰C(O)NR¹²R¹³; —NR¹²R¹³; -cyano; —COOH; —COOR¹⁰;    —C(O)NR¹²R¹³; —C(O)R¹¹; C₁₋₆alkyl; C₂₋₆alkenyl; C₂₋₆alkynyl;    C₆₋₁₀aryl; heterocycle; C₆₋₁₀arylC₁₋₆alkylene;    C₆₋₁₀arylC₂₋₆alkenylene; C₆₋₁₀arylC₂₋₆alkynylene;    heterocycle-C₁₋₆alkylene; heterocycle-C₂₋₆alkenylene; and    heterocycle-C₂₋₆alkynylene; preferably R⁵ is selected from halogen;    —OH; —OR¹⁰; —SH; —SR¹⁰; trifluoromethyl; trifluoromethoxy; nitro;    —NR¹²R¹³; -cyano; —COOH; —COOR¹⁰; —C(O)R¹¹; alkyl; aryl;    heterocycle; arylalkylene; heterocycle-alkylene; preferably R⁵ is    selected from halogen; —OH; —OR¹⁰; —SH; —SR¹⁰; trifluoromethyl;    trifluoromethoxy; nitro; —NR¹²R¹³; -cyano; —COOH; —COOR¹⁰;    —C(O)C₁₋₆alkyl; C₁₋₆alkyl; C₆₋₁₀aryl; heterocycle;    C₆₋₁₀arylC₁₋₆alkylene; preferably R⁵ is selected from halogen;    -cyano; —OH; —OR¹⁰; —SH; —SR¹⁰; trifluoromethyl; trifluoromethoxy;    —C(O)C₁₋₄alkyl; —NR¹²R¹³; C₁₋₆alkyl; phenyl; morpholinyl; preferably    R⁵ is selected from chloro, fluoro; -cyano; —OH; —OR¹⁰; —SH; —SR¹⁰;    trifluoromethyl; trifluoromethoxy; C₁₋₆alkyl; phenyl; morpholinyl;    preferably R⁵ is selected from chloro, fluoro methyl, or cyano;-   n is 1 or 0; preferably n is 1;-   each of Y¹, Y², Y³, Y⁴ and Y⁵ is independently selected from CZ¹; or    N; wherein at least two of Y¹, Y², Y³, Y⁴ and Y⁵ are selected from    CZ¹; preferably each of Y¹, Y², Y³, Y⁴ and Y⁵ is independently    selected from CZ¹; or N; wherein at least three of Y¹, Y², Y³, Y⁴    and Y⁵ are selected from CZ¹; preferably with Z¹ being selected from    hydrogen, alkyl or Z², and Z² is halogen;-   B is selected from aryl; cycloalkyl; and heterocycle; preferably B    is selected from aryl; or heterocycle; preferably B is selected from    C₆₋₁₀aryl; or heterocycle; B is selected from C₆₋₁₀aryl; heteroaryl    or morpholinyl; preferably B is selected from phenyl, pyridyl,    dihydroypyridyl, piperidyl, thiazolyl, tetrahydrothiophenyl, sulfur    oxidized tetrahydrothiophenyl, furanyl, thienyl, pyrrolyl,    pyrazolyl, imidazolyl, tetrazolyl, benzofuranyl, thianaphthalenyl,    indolyl, indolenyl, quinolinyl, isoquinolinyl, benzimidazolyl,    piperidinyl, 4-piperidonyl, pyrrolidinyl, 2-pyrrolidonyl,    pyrrolinyl, tetrahydrofuranyl, bis-tetrahydrofuranyl,    tetrahydropyranyl, bis-tetrahydropyranyl, tetrahydroquinolinyl,    tetrahydroisoquinolinyl, decahydroquinolinyl,    octahydroisoquinolinyl, azocinyl, triazinyl, 6H-1,2,5-thiadiazinyl,    2H,6H-1,5,2-dithiazinyl, thianthrenyl, pyranyl, isobenzofuranyl,    chromenyl, xanthenyl, phenoxathinyl, 2H-pyrrolyl, isothiazolyl,    isoxazolyl, pyrazinyl, pyridazinyl, indolizinyl, isoindolyl,    3H-indolyl, 1H-indazoly, purinyl, 4H-quinolizinyl, phthalazinyl,    naphthyridinyl, quinoxalinyl, quinazolinyl, cinnolinyl, pteridinyl,    4aH-carbazolyl, carbazolyl, β-carbolinyl, phenanthridinyl,    acridinyl, pyrimidinyl, phenanthrolinyl, phenazinyl, phenothiazinyl,    furazanyl, phenoxazinyl, isochromanyl, chromanyl, imidazolidinyl,    imidazolinyl, pyrazolidinyl, pyrazolinyl, piperazinyl, indolinyl,    isoindolinyl, quinuclidinyl, morpholinyl, oxazolidinyl,    benzotriazolyl, benzisoxazolyl, oxindolyl, benzoxazolinyl,    benzothienyl, benzothiazolyl or isatinoyl; preferably B is selected    from phenyl, pyridyl, dihydroypyridyl, piperidyl, thiazolyl,    tetrahydrothiophenyl, sulfur oxidized tetrahydrothiophenyl, furanyl,    thienyl, pyrrolyl, pyrazolyl, imidazolyl, tetrazolyl, benzofuranyl,    thianaphthalenyl, indolyl, indolenyl, quinolinyl, isoquinolinyl,    benzimidazolyl, piperidinyl, 4-piperidonyl, pyrrolidinyl,    2-pyrrolidonyl, pyrrolinyl, tetrahydrofuranyl,    bis-tetrahydrofuranyl, tetrahydropyranyl, bis-tetrahydropyranyl,    pyranyl, 2H-pyrrolyl, pyrazinyl, pyridazinyl, indolizinyl,    isoindolyl, 3H-indolyl, 1H-indazoly, purinyl, pyrimidinyl;    preferably B is selected from phenyl, pyridyl, piperidyl, furanyl,    thienyl, pyrazolyl, imidazolyl, pyrrolidinyl; preferably B is    selected from phenyl, furanyl, or thienyl;-   m is 0, 1, 2 or 3; preferably m is 0, 1 or 2, preferably m is 0 or    1;-   each R⁸ is independently selected from hydrogen; halogen; alkyl;    alkenyl; alkynyl; —OH; —OR²⁰; —SH; trifluoromethyl;    trifluoromethoxy; nitro; -cyano; —COOH; —COOR²⁰; —C(O)NR²²R²³; and    —C(O)R²¹; preferably each R⁸ is independently selected from    hydrogen; halogen; alkyl; —OH; —OR²⁰; —SH; trifluoromethyl;    trifluoromethoxy; nitro; -cyano; preferably each R⁸ is independently    selected from hydrogen; halogen; alkyl; —OR²⁰; trifluoromethyl;    trifluoromethoxy; -cyano; wherein R²⁰ is alkyl; preferably each R⁸    is independently selected from hydrogen; halogen; C₁₋₆alkyl; —OR²⁰;    trifluoromethyl; trifluoromethoxy; -cyano; wherein R²⁰ is C₁₋₆alkyl;    preferably each R⁸ is independently selected from hydrogen; halogen;    C₁₋₄alkyl; —OR²⁰; trifluoromethyl; -cyano; wherein R²⁰ is C₁₋₂alkyl;    preferably each R⁸ is independently selected from hydrogen; fluoro;    chloro; C₁₋₂alkyl; —OCH₃; trifluoromethyl; -cyano;-   each Z¹ is independently selected from hydrogen; C₁₋₆alkyl; and Z²;-   each Z² is independently selected from halogen; —OH; —OR²⁰; —SH;    —SR²⁰; —S(O)R²¹; —S(O)₂R²¹; —SO₂NR²²R²³; trifluoromethyl;    trifluoromethoxy; nitro; —NR²²R²³; -cyano; —COOH; —COOR²⁰; and    —C(O)R²¹; preferably each Z² is independently selected from halogen;    —OH; —OR²⁰; —SH; trifluoromethyl; trifluoromethoxy; —NR²²R²³;    -cyano; —COOH; —COOR²⁰; and —C(O)R²¹; preferably each Z² is    independently selected from halogen; —OH; —OC₁₋₆alkyl;    trifluoromethyl; trifluoromethoxy; -cyano; preferably each Z² is    independently selected from fluoro; chloro; —OH; —OC₁₋₃alkyl;    trifluoromethyl; trifluoromethoxy; -cyano;-   each R¹⁰ is independently selected from alkyl; aryl; heterocycle;    arylalkylene; heterocycle-alkylene; preferably each R¹⁰ is    independently selected from C₁₋₆alkyl; C₆₋₁₀aryl; heterocycle;    C₆₋₁₀arylC₁₋₆alkylene; preferably each R¹⁰ is independently    C₁₋₆alkyl;-   each R¹¹ is independently selected from hydroxyl, alkyl; aryl;    heterocycle; arylalkylene; heterocycle-alkylene; preferably each R¹¹    is independently selected from hydroxyl; C₁₋₆alkyl; C₆₋₁₀aryl;    heterocycle; C₆₋₁₀arylC₁₋₆alkylene; preferably each R¹¹ is    independently from hydroxyl or C₁₋₆alkyl;-   each R¹² and R¹³ is independently selected from hydrogen; alkyl;    aryl; heterocycle; arylalkylene; heterocycle-alkylene; and wherein    R¹² and R¹³ can be taken together in order to form a 4-, 5-, or 6-,    membered heterocycle; preferably each R¹² and R¹³ is independently    selected from hydrogen; alkyl; aryl; heterocycle; arylalkylene;    preferably each R¹² and R¹³ is independently selected from hydrogen;    C₁₋₆alkyl; C₆₋₁₀aryl; heterocycle;-   each R²⁰ is independently selected from alkyl; preferably each R²⁰    is independently selected from C₁₋₆alkyl; preferably each R²⁰ is    independently selected from C₁₋₄alkyl;-   each R²¹ is independently selected from alkyl; preferably each R²¹    is independently selected from C₁₋₆alkyl; preferably each R²¹ is    independently selected from C₁₋₄alkyl;-   each R²² and R²³ is independently selected from hydrogen; or alkyl;    and wherein R²² and R²³ can be taken together in order to form a 4-,    5-, or 6-, membered non-aromatic heterocycle; preferably each R²²    and R²³ is independently selected from hydrogen; or alkyl;    preferably each R²² and R²³ is independently selected from hydrogen;    or C₁₋₆alkyl .

According to an embodiment, the present invention provides compounds ofFormula (AA1), (A1), (A2), (A3), (B1), (B2), (B3), (C1), (C2), (C3),(F1), (F2), (F3), (F4), (F5), (G1), (G2), (G3), (G4), (G5), (G6), (G7),(G8), (H1), (H2), (H3), (H4), (I1), (I2), (I3), (I4), (J1), (J2), (J3),or (J4) or any subgroup thereof, wherein E is CR³,

-   each R¹, R⁴ and R⁶ is independently selected from hydrogen; halogen;    —OH; —OR¹⁰; —SH; trifluoromethyl; trifluoromethoxy; nitro; —NR¹²R¹³;    -cyano; —COOH; —COOR¹⁰; C₁₋₆alkyl; C₆₋₁₀aryl; heterocycle;    C₆₋₁₀arylC₁₋₆alkylene; heterocycle-C₁₋₆alkylene;-   R³ is selected from hydrogen; halogen; —OH; —OR¹⁰; —SH;    trifluoromethyl; trifluoromethoxy; nitro; —NR¹²R¹³; -cyano; —COOH;    —COOR¹⁰; C₁₋₆alkyl; C₆₋₁₀aryl; heterocycle; C₆₋₁₀arylC₁₋₆alkylene;    heterocycle-C₁₋₆alkylene;-   R² is selected from hydrogen; or C₁₋₆alkyl;-   R⁵ is selected from halogen; —OH; —OR¹⁰; —SH; —SR¹⁰;    trifluoromethyl; trifluoromethoxy; nitro; —NR¹²R¹³; -cyano; —COOH;    —COOR¹⁰; —C(O)R¹¹; alkyl; aryl; heterocycle; arylalkylene;    heterocycle-alkylene;-   n is 1;-   each of Y¹, Y², Y³, Y⁴ and Y⁵ is independently selected from CZ¹; or    N; wherein at least three of Y¹, Y², Y³, Y⁴ and Y⁵ are selected from    CZ¹;-   B is selected from aryl; or heterocycle; preferably B is selected    from C₆₋₁₀aryl; or heterocycle; B is selected from C₆₋₁₀aryl;    heteroaryl or morpholinyl; preferably B is selected from phenyl,    pyridyl, dihydroypyridyl, piperidyl, thiazolyl,    tetrahydrothiophenyl, sulfur oxidized tetrahydrothiophenyl, furanyl,    thienyl, pyrrolyl, pyrazolyl, imidazolyl, tetrazolyl, benzofuranyl,    thianaphthalenyl, indolyl, indolenyl, quinolinyl, isoquinolinyl,    benzimidazolyl, piperidinyl, 4-piperidonyl, pyrrolidinyl,    2-pyrrolidonyl, pyrrolinyl, tetrahydrofuranyl,    bis-tetrahydrofuranyl, tetrahydropyranyl, bis-tetrahydropyranyl,    tetrahydroquinolinyl, tetrahydroisoquinolinyl, decahydroquinolinyl,    octahydroisoquinolinyl, azocinyl, triazinyl, 6H-1,2,5-thiadiazinyl,    2H,6H-1,5,2-dithiazinyl, thianthrenyl, pyranyl, isobenzofuranyl,    chromenyl, xanthenyl, phenoxathinyl, 2H-pyrrolyl, isothiazolyl,    isoxazolyl, pyrazinyl, pyridazinyl, indolizinyl, isoindolyl,    3H-indolyl, 1H-indazoly, purinyl, 4H-quinolizinyl, phthalazinyl,    naphthyridinyl, quinoxalinyl, quinazolinyl, cinnolinyl, pteridinyl,    4aH-carbazolyl, carbazolyl, β-carbolinyl, phenanthridinyl,    acridinyl, pyrimidinyl, phenanthrolinyl, phenazinyl, phenothiazinyl,    furazanyl, phenoxazinyl, isochromanyl, chromanyl, imidazolidinyl,    imidazolinyl, pyrazolidinyl, pyrazolinyl, piperazinyl, indolinyl,    isoindolinyl, quinuclidinyl, morpholinyl, oxazolidinyl,    benzotriazolyl, benzisoxazolyl, oxindolyl, benzoxazolinyl,    benzothienyl, benzothiazolyl or isatinoyl; preferably B is selected    from phenyl, pyridyl, dihydroypyridyl, piperidyl, thiazolyl,    tetrahydrothiophenyl, sulfur oxidized tetrahydrothiophenyl, furanyl,    thienyl, pyrrolyl, pyrazolyl, imidazolyl, tetrazolyl, benzofuranyl,    thianaphthalenyl, indolyl, indolenyl, quinolinyl, isoquinolinyl,    benzimidazolyl, piperidinyl, 4-piperidonyl, pyrrolidinyl,    2-pyrrolidonyl, pyrrolinyl, tetrahydrofuranyl,    bis-tetrahydrofuranyl, tetrahydropyranyl, bis-tetrahydropyranyl,    pyranyl, 2H-pyrrolyl, pyrazinyl, pyridazinyl, indolizinyl,    isoindolyl, 3H-indolyl, 1H-indazoly, purinyl, pyrimidinyl;    preferably B is selected from phenyl, pyridyl, piperidyl, furanyl,    thienyl, pyrazolyl, imidazolyl, pyrrolidinyl; preferably B is    selected from phenyl, furanyl, or thienyl;-   m is 0, 1 or 2,-   each R⁸ is independently selected from hydrogen; halogen; alkyl;    —OH; —OR²⁰; —SH; trifluoromethyl; trifluoromethoxy; nitro; -cyano;-   each Z¹ is independently selected from hydrogen; C₁₋₆alkyl; and Z²;-   each Z² is independently selected from halogen; —OH; —OR²⁰; —SH;    trifluoromethyl; trifluoromethoxy; —NR²²R²³; -cyano; —COOH; —COOR²⁰;    and —C(O)R²¹;-   each R¹⁰ is independently selected from C₁₋₆alkyl; C₆₋₁₀aryl;    heterocycle; C₆₋₁₀arylC₁₋₆alkylene;-   each R¹¹ is independently selected from hydroxyl; C₁₋₆alkyl;    C₆₋₁₀aryl; heterocycle; C₆₋₁₀arylC₁₋₆alkylene;-   each R¹² and R¹³ is independently selected from hydrogen; alkyl;    aryl; heterocycle; arylalkylene;-   each R²⁰ is independently selected from C₁₋₆alkyl;-   each R²¹ is independently selected from C₁₋₆alkyl;

According to an embodiment, the present invention provides compounds ofFormula (AA1), (A1), (A2), (A3), (B1), (B2), (B3), (C1), (C2), (C3),(F1), (F2), (F3), (F4), (F5), (G1), (G2), (G3), (G4), (G5), (G6), (G7),(G8), (H1), (H2), (H3), (H4), (I1), (I2), (I3), (I4), (J1), (J2), (J3),or (J4) or any subgroup thereof, wherein E is CR³,

-   each R¹, R⁴ and R⁶ is independently selected from hydrogen; halogen;    —OH; —OC₁₋₄alkyl; trifluoromethyl; trifluoromethoxy; -cyano;    C₁₋₄alkyl; C₆aryl; C₆arylC₁₋₆alkylene;-   R³ is selected from hydrogen; halogen; —OH; —OC₁₋₄alkyl;    trifluoromethyl; trifluoromethoxy; -cyano; C₁₋₄alkyl; C₆aryl;    C₆arylC₁₋₆alkylene;-   R² is selected from hydrogen; or C₁₋₂alkyl;-   R⁵ is selected from halogen; —OH; —OR¹⁰; —SH; —SR¹⁰;    trifluoromethyl; trifluoromethoxy; nitro; —NR¹²R¹³; -cyano; —COOH;    —COOR¹⁰; —C(O)C₁₋₆alkyl; C₁₋₆alkyl; C₆₋₁₀aryl; heterocycle;    C₆₋₁₀arylC₁₋₆alkylene;-   n is 1;-   each of Y¹, Y², Y³, Y⁴ and Y⁵ is independently selected from CZ¹; or    N; wherein at least three of Y¹, Y², Y³, Y⁴ and Y⁵ are selected from    CZ¹, with Z¹ being selected from hydrogen, alkyl or halogen;-   B is selected from C₆₋₁₀aryl; heteroaryl or morpholinyl; preferably    B is selected from phenyl, pyridyl, dihydroypyridyl, piperidyl,    thiazolyl, tetrahydrothiophenyl, sulfur oxidized    tetrahydrothiophenyl, furanyl, thienyl, pyrrolyl, pyrazolyl,    imidazolyl, tetrazolyl, benzofuranyl, thianaphthalenyl, indolyl,    indolenyl, quinolinyl, isoquinolinyl, benzimidazolyl, piperidinyl,    4-piperidonyl, pyrrolidinyl, 2-pyrrolidonyl, pyrrolinyl,    tetrahydrofuranyl, bis-tetrahydrofuranyl, tetrahydropyranyl,    bis-tetrahydropyranyl, tetrahydroquinolinyl,    tetrahydroisoquinolinyl, decahydroquinolinyl,    octahydroisoquinolinyl, azocinyl, triazinyl, 6H-1,2,5-thiadiazinyl,    2H,6H-1,5,2-dithiazinyl, thianthrenyl, pyranyl, isobenzofuranyl,    chromenyl, xanthenyl, phenoxathinyl, 2H-pyrrolyl, isothiazolyl,    isoxazolyl, pyrazinyl, pyridazinyl, indolizinyl, isoindolyl,    3H-indolyl, 1H-indazoly, purinyl, 4H-quinolizinyl, phthalazinyl,    naphthyridinyl, quinoxalinyl, quinazolinyl, cinnolinyl, pteridinyl,    4aH-carbazolyl, carbazolyl, β-carbolinyl, phenanthridinyl,    acridinyl, pyrimidinyl, phenanthrolinyl, phenazinyl, phenothiazinyl,    furazanyl, phenoxazinyl, isochromanyl, chromanyl, imidazolidinyl,    imidazolinyl, pyrazolidinyl, pyrazolinyl, piperazinyl, indolinyl,    isoindolinyl, quinuclidinyl, morpholinyl, oxazolidinyl,    benzotriazolyl, benzisoxazolyl, oxindolyl, benzoxazolinyl,    benzothienyl, benzothiazolyl or isatinoyl; preferably B is selected    from phenyl, pyridyl, dihydroypyridyl, piperidyl, thiazolyl,    tetrahydrothiophenyl, sulfur oxidized tetrahydrothiophenyl, furanyl,    thienyl, pyrrolyl, pyrazolyl, imidazolyl, tetrazolyl, benzofuranyl,    thianaphthalenyl, indolyl, indolenyl, quinolinyl, isoquinolinyl,    benzimidazolyl, piperidinyl, 4-piperidonyl, pyrrolidinyl,    2-pyrrolidonyl, pyrrolinyl, tetrahydrofuranyl,    bis-tetrahydrofuranyl, tetrahydropyranyl, bis-tetrahydropyranyl,    pyranyl, 2H-pyrrolyl, pyrazinyl, pyridazinyl, indolizinyl,    isoindolyl, 3H-indolyl, 1H-indazoly, purinyl, pyrimidinyl;    preferably B is selected from phenyl, pyridyl, piperidyl, furanyl,    thienyl, pyrazolyl, imidazolyl, pyrrolidinyl; preferably B is    selected from phenyl, furanyl, or thienyl;-   m is 0, 1 or 2,-   each R⁸ is independently selected from hydrogen; halogen; alkyl;    —OR²⁶; trifluoromethyl; trifluoromethoxy; -cyano; wherein R²⁰ is    alkyl;-   each Z¹ is independently selected from hydrogen; C₁₋₆alkyl; and Z²;-   each Z² is independently selected from halogen; —OH;    trifluoromethyl; trifluoromethoxy; -cyano;-   each R¹⁰ is independently C₁₋₆alkyl;-   each R¹² and R¹³ is independently selected from hydrogen; C₁₋₆alkyl;    C₆₋₁₀aryl; heterocycle-   each R²⁰ is independently selected from C₁₋₄alkyl.

According to an embodiment, the present invention provides compounds ofFormula (AA1), (A1), (A2), (A3), (B1), (B2), (B3), (C1), (C2), (C3),(F1), (F2), (F3), (F4), (F5), (G1), (G2), (G3), (G4), (G5), (G6), (G7),(G8), (H1), (H2), (H3), (H4), (I1), (I2), (I3), (I4), (J1), (J2), (J3),or (J4) or any subgroup thereof, wherein E is CR³,

-   each R¹, R⁴ and R⁶ is independently selected from hydrogen; fluoro;    or chloro;-   R³ is selected from hydrogen; halogen; —OH; methoxy;    trifluoromethyl; trifluoromethoxy; -cyano; C₁₋₄alkyl; C₆aryl;-   R² is hydrogen;-   R⁵ is selected from halogen; -cyano; —OH; —OR¹⁰; —SH; —SR¹⁰;    trifluoromethyl; trifluoromethoxy; —C(O)C₁₋₄alkyl; —NR¹²R¹³;    C₁₋₆alkyl; phenyl; morpholinyl;-   n is 1-   each of Y¹, Y², Y³, Y⁴ and Y⁵ is independently selected from CZ¹; or    N; wherein at least three of Y¹, Y², Y³, Y⁴ and Y⁵ are selected from    CZ¹, with Z¹ being selected from hydrogen, or halogen;-   B is selected from phenyl, pyridyl, dihydroypyridyl, piperidyl,    thiazolyl, tetrahydrothiophenyl, sulfur oxidized    tetrahydrothiophenyl, furanyl, thienyl, pyrrolyl, pyrazolyl,    imidazolyl, tetrazolyl, benzofuranyl, thianaphthalenyl, indolyl,    indolenyl, quinolinyl, isoquinolinyl, benzimidazolyl, piperidinyl,    4-piperidonyl, pyrrolidinyl, 2-pyrrolidonyl, pyrrolinyl,    tetrahydrofuranyl, bis-tetrahydrofuranyl, tetrahydropyranyl,    bis-tetrahydropyranyl, pyranyl, 2H-pyrrolyl, pyrazinyl, pyridazinyl,    indolizinyl, isoindolyl, 3H-indolyl, 1H-indazoly, purinyl,    pyrimidinyl; preferably B is selected from phenyl, pyridyl,    piperidyl, furanyl, thienyl, pyrazolyl, imidazolyl, pyrrolidinyl;    preferably B is selected from phenyl, furanyl, or thienyl;-   m is 0, 1 or 2, preferably m is 0 or 1;-   each R⁸ is independently selected from hydrogen; halogen; C₁₋₄alkyl;    —OR²⁰; trifluoromethyl; -cyano; wherein R²⁰ is C₁₋₂alkyl; preferably    each R⁸ is independently selected from hydrogen; fluoro; chloro;    C₁₋₂alkyl; —OCH₃; trifluoromethyl; -cyano;-   each Z¹ is independently selected from hydrogen; C₁₋₆alkyl; and Z²;-   each Z² is independently selected from fluoro; chloro; —OH;    trifluoromethyl; trifluoromethoxy; -cyano;-   each R¹⁰ is independently C₁₋₆alkyl;-   each R¹² and R¹³ is independently selected from hydrogen; or    C₁₋₆alkyl.    The present invention also encompasses a pharmaceutical composition    comprising one or more pharmaceutically acceptable excipients and a    therapeutically effective amount of a compound according to the    formulae herein such as (AA1), (A1) or any subgroup or embodiment    thereof or a stereoisomer, enantiomer or tautomer thereof.

The present invention also encompasses compounds of the formulae hereinor any subgroup or embodiment thereof or a stereoisomer, enantiomer,tautomer, solvate, hydrate, salt or prodrug thereof for use as amedicine.

The present invention also encompasses compounds of formulae herein orof any subgroup or embodiment thereof or a stereoisomer, enantiomer,tautomer, solvate, hydrate, salt or prodrug thereof for use as amedicine for the prevention or treatment of neurodegenerative disorders.

In a particular embodiment, the invention provides the compoundsdescribed herein for use as a medicine for the prevention or treatmentof neurodegenerative disorders, such as disorders collectively known astauopathies, and disorders characterised by cytotoxic α-synucleinamyloidogenesis. The invention also provides for pharmaceuticalcompositions of the compounds described herein and methods for thetreatment or prevention of neurodegenerative disorders.

The term “tauopathy” as used herein, unless otherwise stated, refers toa disease characterised by dysfunctioning of the TAU protein, forinstance manifested by insoluble aggregates or polymers of said protein.Such diseases include, but are not limited to, Alzheimer's disease,Pick's disease, corticobasal degeneration, progressive supranuclearpalsy, frontotemporal dementia and parkinsonism (linked to chromosome17, FTDP-17).

The term “α-synucleopathy” as used herein, unless otherwise stated,refers to a disease characterised by the presence of pathologicaldeposition of insoluble α-synuclein polymers or aggregatesintracellularly and/or extracellularly. Such diseases include, but arenot limited to, Parkinson's disease, diffuse Lewy body disease,traumatic brain injury, amyotrophic lateral sclerosis, Niemann-Pickdisease, Hallervorden-Spatz syndrome, Down syndrome, neuroaxonaldystrophy, and multiple system atrophy.

The term “neurodegenerative disorders” as used herein, unless otherwisestated, refers to tauopathy and α-synucleopathy, and thereby includes,but is not limited to Alzheimer's disease, Pick's disease, corticobasaldegeneration, progressive supranuclear palsy, frontotemporal dementia,parkinsonism (linked to chromosome 17, FTDP-17), Parkinson's disease,diffuse Lewy body disease, traumatic brain injury, amyotrophic lateralsclerosis, Niemann-Pick disease, Hallervorden-Spatz syndrome, Downsyndrome, neuroaxonal dystrophy, and multiple system atrophy.

As used herein, the term “Parkinson's disease” refers to a chronicprogressive nervous disease characterised by neurodegeneration,especially degeneration of dopaminergic neurons. Symptoms includestooped posture, resting tremor, weakness of resting muscles, ashuffling gait, speech impediments, movement difficulties and aneventual slowing of mental processes and dementia.

The term “Alzheimer's disease” as used herein, also called Alzheimerdisease, Senile Dementia of the Alzheimer Type (SDAT) or simplyAlzheimer's refers to a chronic progressive nervous diseasecharacterised by neurodegeneration with as most important (early)symptom being memory loss. As the disease advances, symptoms includeconfusion, irritability and aggression, mood swings, language breakdown,long-term memory loss, and the general withdrawal of the sufferer astheir senses decline.

The term “neuroprotective” agent, as used herein, refers to drugs orchemical agents intended to prevent neurodegeneration, including drugsthat slow down or stop the progression of neuronal degeneration.

The present invention relates to a group of novel compounds which havedesirable biological properties such as an inhibitory effect onTAU-instigated cytotoxicity. Based on this inhibitory activity, and thefact that these compounds are not toxic to neural cells, thesederivatives are useful in the manufacture of a medicament for theprevention and/or treatment of a tauopathy. The novel compounds have astructure according to formulae and embodiments thereof as describedherein.

The term “pharmaceutically acceptable carrier” or “pharmaceuticallyacceptable excipient” as used herein in relation to pharmaceuticalcompositions and combined preparations means any material or substancewith which the active principle may be formulated in order to facilitateits application or dissemination to the locus to be treated, forinstance by dissolving, dispersing or diffusing the said composition,and/or to facilitate its storage, transport or handling withoutimpairing its effectiveness. The pharmaceutically acceptable carrier maybe a solid or a liquid or a gas which has been compressed to form aliquid, i.e. the compositions of this invention can suitably be used asconcentrates, emulsions, solutions, granulates, dusts, sprays, aerosols,pellets or powders.

Suitable pharmaceutical carriers for use in the said pharmaceuticalcompositions and their formulation are well known to those skilled inthe art. There is no particular restriction to their selection withinthe present invention although, due to the usually low or very lowwater-solubility of the derivatives of this invention, special attentionwill be paid to the selection of suitable carrier combinations that canassist in properly formulating them in view of the expected time releaseprofile. Suitable pharmaceutical carriers include additives such aswetting agents, dispersing agents, stickers, adhesives, emulsifying orsurface-active agents, thickening agents, complexing agents, gellingagents, solvents, coatings, antibacterial and antifungal agents (forexample phenol, sorbic acid, chlorobutanol), isotonic agents (such assugars or sodium chloride) and the like, provided the same areconsistent with pharmaceutical practice, i.e. carriers and additiveswhich do not create permanent damage to mammals.

The pharmaceutical compositions of the present invention may be preparedin any known manner, for instance by homogeneously mixing, dissolving,spray-drying, coating and/or grinding the active ingredients, in aone-step or a multi-steps procedure, with the selected carrier materialand, where appropriate, the other additives such as surface-activeagents. may also be prepared by micronisation, for instance in view toobtain them in the form of microspheres usually having a diameter ofabout 1 to 10 μm, namely for the manufacture of microcapsules forcontrolled or sustained release of the biologically activeingredient(s).

Methods of preparing various pharmaceutical compositions with a certainamount of active ingredient are known, or will be apparent in light ofthis disclosure, to those skilled in this art. For examples of methodsof preparing pharmaceutical compositions, see (Remington; The Scienceand Practice of Pharmacy, Lippincott Williams & Wilkins, 21st Ed, 2005).

Therapeutically effective doses of the compounds of the presentinvention required to prevent or to treat the medical condition arereadily ascertained by one of ordinary skill in the art usingpreclinical and clinical approaches familiar to the medicinal arts. Thedose of the compound or a pharmaceutically acceptable salts thereof tobe administered depends on the individual case and, as customary, is tobe adapted to the conditions of the individual case for an optimumeffect. Thus it depends, of course, on the frequency of administrationand on the potency and duration of action of the compound employed ineach case for therapy or prophylaxis, but also on the nature andseverity of the disease and symptoms, and on the sex, age, weightco-medication and individual responsiveness of the subject to be treatedand on whether the therapy is acute or prophylactic. The percentage ofdrug present in the formulation is also a factor. Doses may be adaptedin function of weight and for pediatric applications. In the case oforal administration the dosage for adults can vary from about 0.01 mg toabout 4000 mg per day, preferably from about 0.1 mg to about 2000 mg perday, more preferably from about 0.5 mg to about 1000 mg per day, of acompound of the invention or of the corresponding amount of apharmaceutically acceptable salt thereof. The daily dosage may beadministered as single dose or in divided doses and, in addition, theupper limit can also be exceeded when this is found to be indicated.

The novel compounds of the invention can be prepared by the followingmethods which are exemplified further in the examples.

The compounds of the invention can be prepared while using a series ofchemical reactions well known to those skilled in the art, altogethermaking up the process for preparing said compounds and exemplifiedfurther. The processes described further are only meant as examples andby no means are meant to limit the scope of the present invention.

The compounds of the present invention can be prepared according to thefollowing general procedures:

Scheme 1: all R¹, R², R³, R⁴, R⁵, R⁶, R⁸, Y¹, Y², Y³, Y⁴, Y⁵, B, n, mand LG are as described for the compounds of the present invention andits embodiments and formulae.

Intermediates of formula I are commercially available or synthesized byprocedures known to the skilled in the art or as set forth in theexamples below. More detailed information can be found in the followingreferences (e.g., Journal of Fluorine Chemistry, 127(9), 1256-1260,2006; Medicinal Chemistry, 3(6), 561-571, 2007; WO 2006007542; J. Org.Chem., 71(18), 7028-7034, 2006; Organic Letters, 4(16), 2613-2615, 2002;Tetrahedron Letters, 43(5), 787-790, 2002; Synlett, 8, 1311-1315, 2005;Journal of the American Chemical Society, 130(12), 3853-3865, 2008;Journal of Medicinal Chemistry, 49(21), 6408-6411, 2006; Journal ofMedicinal Chemistry, 47(15), 3823-3842, 2004).

Condensation of intermediates of formula I with intermediates of formulaII (commercially available or synthesized by procedures known to theskilled in the art or as set forth in the examples below), by proceduresknown to the skilled in the art or as set forth in the examples belowprovides compounds of formula III. In a similar manner, condensation ofintermediates of formula I with intermediates of formula IV(commercially available or synthesized by procedures known to theskilled in the art or as set forth in the examples below), by proceduresknown to the skilled in the art or as set forth in the examples below,provides intermediates of formula VI, which can be subsequentlyconverted in compounds of formula II with a suitable precursor ofintermediate of formula V by procedures known to the skilled in the artor as set forth in the examples below.

The strategy outlined in scheme 1 can be applied for the synthesis ofany aromatic 6 membered ring systems (e.g., benzene, pyridine,pyrimidine, pyridazine, pyrazine) and is not limited to these examples.

The resulting compounds may be optionally converted into apharmaceutically acceptable salt or vice versa according to the methodsknown by the skilled in the art.

Further, the resulting compounds may be converted into each otherfollowing art-known functional group transformation reactions. Forexample, amino groups may be N-alkylated, nitro groups reduced to aminogroups, a halo atom may be exchanged for another halo.

Another aspect of the present invention therefore provides intermediatesof formula VI

wherein R¹, R², R³, R⁴, R⁵, R⁶, Y¹, Y², Y³, Y⁴, Y⁵, n, and LG are eachas defined herein, and the isomers (in particular stereoisomers,enantiomers or tautomers), solvates, hydrates, or salts thereof.

Another aspect of the present invention relates to a method of preparingnew intermediates of formula VI, as depicted above, wherein R¹, R², R³,R⁴, R⁵, R⁶, Y¹, Y², Y³, Y⁴, Y⁵, n, and LG are each as defined herein,and the isomers (in particular stereoisomers, enantiomers or tautomers),solvates, hydrates, or salts thereof; by condensation of intermediatesof formula I with intermediates of formula IV (commercially available orsynthesized by procedures known to the skilled in the art or as setforth in the examples below), by procedures known to the skilled in theart or as set forth in the examples below.

EXAMPLES

The following examples are provided for the purpose of illustrating thepresent invention and by no means should be interpreted to limit thescope of the present invention.

Part A represents the preparation of the compounds (intermediates andfinal compounds) whereas Part B represents the pharmacological examples.

All the preparative HPLC purifications mentioned in this experimentalpart have been carried out with the following system: a Waters 2489UV/Visible Detector, a Waters 2545 Binary Gradient Module, a WatersFraction Collector III and a Waters Dual Flex Injector.

The separations were performed with a X-Bridge Prep C18, 100×19 mm, 5 μmcolumn equipped with a X-Bridge C18, 5 μm, 19×10 mm Guard column.

Elutions were carried out with the methods described in the followingtables, and detection wavelengths were fixed at 210 and 254 nm.

Solvent A: Ammonium Acetate puriss p.a. for HPLC 10 mM in milliQ water,adjusted at pH10 with ammonium hydroxide puriss p.a. for HPLC.

Solvent B: acetonitrile HPLC grade.

HPLC Method 1

Time Flow Rate (min) ml/min Solvent A % Solvent B % 0 20 60 40 2.00 2060 40 7.00 20 20 80 7.10 20 10 90 10.00 20 10 90 10.50 20 60 40 16.00 2060 40

HPLC Method 2

Time Flow Rate (min) ml/min Solvent A % Solvent B % 0 20 50 50 2.00 2050 50 9.00 20 10 90 11.00 20 10 90 11.20 20 50 50 16.00 20 50 50

Exemplary compounds of the present invention are shown in table 1.

TABLE 1 CODE STRUCTURE Cpd001

Cpd002

Cpd003

Cpd004

Cpd005

Cpd006

Cpd007

Cpd008

Cpd009

Cpd010

Cpd011

Cpd012

Cpd013

Cpd014

Cpd015

Cpd016

Cpd017

Cpd018

Cpd019

Cpd020

Cpd021

Cpd022

Cpd023

Cpd024

Cpd025

Cpd026

Cpd027

Cpd028

Cpd029

Cpd030

Cpd031

Cpd032

Cpd033

Cpd034

Cpd035

Cpd036

Cpd037

Cpd038

Cpd039

Cpd040

Cpd041

Cpd042

Cpd043

Cpd044

Cpd045

Cpd046

Cpd047

Cpd048

Cpd049

Cpd050

Cpd051

Cpd052

Cpd053

Cpd054

Cpd055

Cpd056

Cpd057

Cpd058

Cpd059

Cpd060

Cpd061

Cpd062

Cpd063

Cpd064

Cpd065

Cpd066

Cpd067

Cpd068

Cpd069

Cpd070

Cpd071

Cpd072

Cpd073

Cpd074

Cpd075

Cpd076

Cpd077

Cpd078

Cpd079

Cpd080

Cpd081

Cpd082

Cpd083

Cpd084

Cpd085

Cpd086

Cpd087

Cpd088

Cpd089

Cpd090

Cpd091

Cpd092

Cpd093

Cpd094

Cpd095

Cpd096

Cpd097

Cpd098

Cpd099

Cpd100

Cpd101

Cpd102

Cpd103

Cpd104

Part A Method A

A mixture of 2-(1H-indol-3-yl)alkylamine (1 equivalent), a carboxylicacid (1.1 equivalents), HATU (1.3 equivalents) andN,N-diisopropylethylamine (2.5 equivalents) in DMF (15 mL/mmol) wasstirred at room temperature for 18 hours and concentrated under reducedpressure. The residue was dissolved in ethyl acetate and the organiclayer was washed with water, dried with magnesium sulphate andevaporated to dryness. The crude material was purified by flashchromatography on silica gel to yield the desired compound.

Method B

A mixture of intermediates 1, 2 or 3 (1 equivalent), a boronic acid(1.05 equivalents), sodium carbonate (2 equivalents) andtetrakis(triphenylphosphine)palladium (0.05 equivalents) in water (5mL/mmol) and dimethoxyethane (15 mL/mmol) was irradiated in a microwaveoven at 130° C. for 15 minutes. The resulting mixture was partitionedbetween water and ethyl acetate and the phases were separated. Theorganic layer was washed with water and concentrated under reducedpressure. The crude material was purified by flash chromatography onsilica gel to yield the desired compound.

Method C

Triethylamine (1.2 equivalents) was added to a mixture of a2-(1H-indol-3-yl)alkylamine (1 equivalent) and an acid chloride (1.05equivalents) in dichloromethane (15 mL/mmol) at 0° C. The reactionmixture was allowed to warm at room temperature and stirred untilconsumption of the amine (0.5 to 24 hours). The reaction mixture wasconcentrated under reduced pressure and the crude material was purifiedby flash chromatography on silica gel to yield the desired compound.

Method D Synthesis of Substituted 2-(1H-indol-3-yl)ethanamine Step I:Substituted 2-iodo-aniline

Iodine (1 eq) was added to a stirred mixture of silver sulphate (1 eq)and an aniline (1 eql) in ethanol (6.21 mL/mmol). The reaction mixturewas then stirred at room temperature for 18 hours and filtered overcelite. The solution was concentrated under reduced pressure and theresidue was partitioned between ethyl acetate and a saturated aqueoussolution of sodium thiosulphate. The organic layer was washed withbrine, dried with magnesium sulphate and concentrated under reducedpressure. The crude residue was purified by flash chromatography onsilica gel to yield a substituted 2-iodo-aniline

Step II Substituted 2-(2-(triethylsilyl))-1H-indol-3-yl)ethanol

A 2-iodo-aniline (1 equivalent), 4-(triethylsilyl)but-3-yn-1-ol (1.1equivalents), Bis(diphenylphosphino)ferrocene]palladium(II) chloride(0.05 equivalents), lithium chloride (1 equivalent) and sodium carbonate(2 equivalents) were suspended in DMF (2.87 mL/mmol) and the mixture wasstirred at 100° C. for 15 hours. The solution was concentrated underreduced pressure and diluted in ethyl acetate. The organic layer wassuccessively washed with brine, sodium thiosulphate, dried overmagnesium sulphate and concentrated under reduced pressure. The cruderesidue was purified by flash chromatography on silica gel to yield thetitle compound.

Step III Substituted 3-(2-bromoethyl)-2-(triethylsilyl)-1H-indole

A mixture of 2-(2-(triethylsilyl))-1H-indol-3-yl)ethanol (1 equivalent)in THF (2.8 mL/mmol) was added to a solution of triphenyl phosphine (1.5equivalents) and perbromomethane (1.5 equivalents) in THF (3.76 mL/mmol)pre-stirred for (0.5-1) hour. The resulting mixture was stirred at roomtemperature for 18 hours. The reaction mixture was then filtered andconcentrated under reduced pressure and the crude residue was purifiedby flash chromatography on silica gel to yield the title compound.

Step IV Substituted 3-(2-azidoethyl)-2-(triethylsilyl)-1H-indole

A mixture of 3-(2-bromoethyl)-2-(triethylsilyl)-1H-indole (1 equivalent)and sodium azide (3 equivalents) in DMF (9 mL/mmol) was stirred at 70°C. for 4 hours and concentrated under reduced pressure. The residue wasdiluted in ethyl acetate, washed with brine, dried over magnesiumsulphate and concentrated under reduced pressure to give the titlecompound.

Step V Substituted 2-(1H-indol-3-yl)ethanamine

A mixture of 3-(2-azidoethyl)-2-(triethylsilyl)-1H-indole (1 equivalent)and triphenyl phosphine (1.5 equivalents) in methanol (4.6 mL/mmol) wasstirred at 70° C. for 2 hours. The reaction mixture was concentratedunder reduced pressure and the crude material was dissolved in asolution of tetrabutylamonium fluoride (3 equivalents, 1M) in THF andstirred at room temperature for 18-36 hours and concentrated underreduced pressure. The title compound was used without any furtherpurification.

Examples of the Preparation of Intermediates Intermediate 1-Preparationof N-(2-(5-chloro-1H-indol-3-yl)ethyl)-2-iodobenzamide

N-(2-(5-chloro-1H-indol-3-yl)ethyl)-2-iodobenzamide was preparedaccording to method C with triethylamine (1.19 mL; 8.48 mmol),2-(5-chloro-1H-indol-3-yl)ethanamine hydrochloride (0.800 g; 3.90 mmol)and 2-iodobenzoyl chloride (0.968 g; 3.56 mmol) in dichloromethane (75mL). The mixture was stirred for 20 minutes at room temperature and wasevaporated to dryness. The crude material was purified by flashchromatography on silica gel (eluent 1 to 10% ethyl acetate indichloromethane) to furnish 1.32 g (92%) ofN-(2-(5-chloro-1H-indol-3-yl)ethyl)-2-iodobenzamide as a white solid.

ESI/APCI(+): 425 (M+H), 447 (M+Na); ESI/APCI(−): 423 (M−H).

Intermediate 2-Preparation ofN-(2-(5-chloro-1H-indol-3-yl)ethyl)-3-iodobenzamide

N-(2-(5-chloro-1H-indol-3-yl)ethyl)-3-iodobenzamide was preparedaccording to method C with triethylamine (2.23 mL; 15.90 mmol),2-(5-chloro-1H-indol-3-yl)ethanamine hydrochloride (1.5 g; 6.36 mmol)and 3-iodobenzoyl chloride (1.82 g; 6.68 mmol) in dichloromethane (75mL). The mixture was stirred for 20 minutes at room temperature and wasevaporated under reduced pressure. The crude material was purified byflash chromatography on silica gel (eluent 2 to 20% ethyl acetate indichloromethane) to provide 2.56 g (95%) ofN-(2-(5-chloro-1H-indol-3-yl)ethyl)-3-iodobenzamide as a white solid.

ESI/APCI(+): 425 (M+H), 447 (M+Na); ESI/APCI(−): 423 (M−H).

Intermediate 3—Preparation ofN-(2-(5-chloro-1H-indol-3-yl)ethyl)-4-iodobenzamide

N-(2-(5-chloro-1H-indol-3-yl)ethyl)-4-iodobenzamide was preparedaccording to method C with triethylamine (2.23 mL; 15.90 mmol),2-(5-chloro-1H-indol-3-yl)ethanamine hydrochloride (1.5 g; 6.36 mmol)and 4-iodobenzoyl chloride (1.82 g; 6.68 mmol) in dichloromethane (75mL). The mixture was stirred for 20 minutes at room temperature and wasevaporated under reduced pressure. The crude material was purified byflash chromatography on silica gel (eluent 2 to 20% ethyl acetate indichloromethane) to provide 1.22 g (45%) ofN-(2-(5-chloro-1H-indol-3-yl)ethyl)-4-iodobenzamide as a white solid.

ESI/APCI(+): 425 (M+H), 447 (M+Na); ESI/APCI(−): 423 (M−H).

Intermediate 4—Preparation of (5-Chloro-1H-indol-3-yl)methanamine

A solution of 5-chloro-1H-indole-3-carbaldehyde (0.690 g; 3.76 mmol),hydroxylamine hydrochloride (0.366 g; 5.27 mmol) and sodium acetate(0.463 g; 5.65 mmol) in ethanol (10 mL) was stirred at reflux for 3.5hours. The reaction mixture was concentrated under reduced pressure andthe residue was partitioned between ethyl acetate and brine andextracted with ethyl acetate. The solvent was evaporated and the residue(crude oxime) was dissolved in glacial acetic acid (30 mL). Zinc dust(1.48 g; 22.59 mmol) was added to the solution, and the mixture wasstirred at room temperature for 14 hours. The resulting suspension wasfiltered on a Celite pad and the cake was washed with ethyl acetate. Thefiltrate was concentrated under reduced pressure and the residue waspartitioned between an aqueous solution of sodium carbonate and ethylacetate. The organic layer was dried over magnesium sulphate, filtered,and concentrated to give 0.680 (88%) of(5-Chloro-1H-indol-3-yl)methanamine as a brown solid.

ESI/APCI(+): 164 (M+H—NH₃); ESI/APCI(−): 179 (M−H).

Intermediate 5—Preparation of6-chloro-N-(2-(5-chloro-1H-indol-3-yl)ethyl)pyridazine-3-carboxamide

Thionyl chloride (0.092 mL; 0.150 mmol) was added to a suspension of6-chloropyridazine-3-carboxylic acid (0.100 g; 0.630 mmol) in chloroform(1 mL); the resulting mixture was refluxed for 18 hours and concentratedunder reduced pressure. The residue was dissolved in dichloromethane (3mL) and 2-(5-chloro-1H-indol-3-yl)ethanamine hydrochloride (0.160 g;0.693 mmol) and N-ethyl-N-isopropylpropan-2-amine (0.271 mL; 1.58 mmol)were added. The resulting green solution was stirred at room temperaturefor 2 hours, diluted with dichloromethane and successively washed withsodium hydrogen sulphate (1M), sodium carbonate (1M) and brine, driedover magnesium sulphate and the crude material was purified by flashchromatography on silica gel (eluent 10 to 60% ethyl acetate indichloromethane) to yield 0.048 g (23%) of6-chloro-N-(2-(5-chloro-1H-indol-3-yl)ethyl)pyridazine-3-carboxamide.

ESI/APCI(+): 335 (M+H), 357 (M+Na); ESI/APCI(+): 333 (M−H).

Intermediate 6—Preparation of 3-(5-Chloro-1H-indol-3-yl)propan-1-ol

A mixture of (4-chlorophenyl)hydrazine hydrochloride (5.26 g; 28.50mmol) and 3,4-dihydro-2H-pyran (2.63 mL; 28.50 mmol) in a mixture ofwater (9 mL) and dioxane (36 mL) was stirred at 100° C. for 48 hours.After cooling to room temperature the mixture was diluted with ethylacetate. The aqueous layer was separated and extracted with ethylacetate. The combined organic layers were dried over magnesium sulphate,and concentrated under reduced pressure. The residue was purified byflash chromatography on silica gel (eluent: 0 to 6% methanol indichloromethane) to afford 3.85 g (64%) of3-(5-Chloro-1H-indol-3-yl)propan-1-ol as an oily residue.

ESI/APCI(+): 210 (M+H); ESI/APCI(−): 208 (M−H).

Intermediate 7—Preparation of 3-(3-Bromopropyl)-5-chloro-1H-indole

Carbon tetrabromine (2.37 g; 7.15 mmol) was added to the solution oftriphenylphosphine (1.90 g; 7.15 mmol) in tetrahydrofuran (20 mL) andthe mixture was stirred at room temperature for 15 min. A solution of3-(5-Chloro-1H-indol-3-yl)propan-1-ol (1 g; 4.77 mmol) intetrahydrofuran (12 mL) was then added to the green suspension and theresulting reaction mixture was stirred for 18 hours at room temperature.The solution was concentrated under reduced pressure, and the residuewas purified by flash chromatography on silica gel (eluent: 2 to 40%ethyl acetate in heptane) to afford 0.791 g, (61%) of3-(3-Bromopropyl)-5-chloro-1H-indole as a dark oily residue.

¹H NMR (DMSO-d₆) δ 11.04 (s, 1H); 7.56 (d, 1H); 7.35 (d, 1H); 7.24 (d,1H); 7.06 (dd, 1H, 3.54 (t, 2H); 2.80 (t, 2H); 2.13 (quint, 2H).

Intermediate 8—Preparation of 3-(3-Azidopropyl)-5-chloro-1H-indole

A mixture of 3-(3-Bromopropyl)-5-chloro-1H-indole (0.730 g; 2.68 mmol)and sodium azide (0.522 g; 8.03 mmol) was stirred in DMF (5 mL) for 18hours and was then concentrated under reduced pressure. The residue waspartitioned between water and dichloromethane. After separation, theorganic layer was dried over magnesium sulphate and the volatiles wereevaporated under reduced pressure to yield quantitatively3-(3-Azidopropyl)-5-chloro-1H-indole as an oily residue which was usedwithout purification.

Intermediate 9—Preparation of 3-(5-Chloro-1H-indol-3-yl)propan-1-amine

To a solution of 3-(3-Azidopropyl)-5-chloro-1H-indole (0.299 g; 1.27mmol) in THF (9 mL) were added triphenylphosphine (0.354 g; 1.34 mmol)and water (0.6 mL). The reaction mixture was stirred at room temperaturefor 22 hours and was then concentrated under reduced pressure. Theresidue was dissolved in dichloromethane (10 mL) and 10 mL of 6Nhydrochloric acid were added. After separation, the aqueous layer wasfurther extracted with dichloromethane (2×10 mL) and the pH was adjustedto 14 with an aqueous solution of sodium hydroxide 6N. This basicsolution was extracted dichloromethane (3×20 mL) and the combinedorganic layer was dried over magnesium sulphate, and evaporated toafford 0.089 g (34%) of 3-(5-Chloro-1H-indol-3-yl)propan-1-amine as awhite solid.

ESI/APCI(+): 209 (M+H); ESI/APCI(−): 207 (M−H).

Intermediate 10—Preparation of 2-iodo-4-(trifluoromethyl)aniline

2-iodo-4-(trifluoromethyl)aniline was prepared according to method DStep I with iodine (1.58 g; 6.21 mmol), silver sulphate (1.94 g; 6.21mmol) and 4-(trifluoromethyl)aniline (0.8 mL; 6.21 mmol) in ethanol (40mL). The crude residue was purified by flash chromatography on silicagel (eluent 2 to 40% ethyl acetate in heptane) to afford 1.08 g (61%) of2-iodo-4-(trifluoromethyl)aniline as a red oil.

¹H NMR (DMSO-d₆) δ 7.80 (s, 1H), 7.38 (d, 1H), 6.82 (d, 2H), 5.93 (s,2H).

Intermediate 11—Preparation of2-(2-(triethylsilyl)-5-(trifluoromethyl)-1H-indol-3-yl)ethanol

2-(2-(triethylsilyl)-5-(trifluoromethyl)-1H-indol-3-yl)ethanol wasprepared according to method D Step II with2-iodo-4-(trifluoromethyl)aniline (1.0 g; 3.48 mmol),4-(triethylsilyl)but-3-yn-1-ol (0.807 mL; 3.83 mmol),Bis(diphenylphosphino)ferrocene]palladium(II) chloride (0.142 g; 0.174mmol), lithium chloride (0.147 g; 3.48 mmol) and sodium carbonate (0.738g; 6.97 mmol) in DMF (10 mL). The crude mixture was purified by flashchromatography on silica gel (eluent 2 to 40% ethyl acetate in heptane)to afford 0.733 g (61%) of2-(2-(triethylsilyl)-5-(trifluoromethyl)-1H-indol-3-yl)ethanol as ayellow oil.

ESI/APCI(+):344 (M+H); ESI/APCI(−): 343 (M−H).

Intermediate 12—Preparation of3-(2-bromoethyl)-2-(triethylsilyl)-5-(trifluoromethyl)-1H-indole

3-(2-bromoethyl)-2-(triethylsilyl)-5-(trifluoromethyl)-1H-indole wasprepared according to method D Step III with2-(2-(triethylsilyl)-5-(trifluoromethyl)-1H-indol-3-yl)ethanol (0.730 g;2.13 mmol) in THF (6 mL); triphenyl phosphine (0.836 g; 3.19 mmol) andperbromomethane (1.06 g; 3.19 mmol) in THF (12 mL) pre-stirred for 1hour. The crude residue was purified by flash chromatography on silicagel (eluent 5 to 40% ethyl acetate in heptane) to afford 0.449 g (52%)of 3-(2-bromoethyl)-2-(triethylsilyl)-5-(trifluoromethyl)-1H-indole as ayellow oil.

Intermediate 13—Preparation of3-(2-azidoethyl)-2-(triethylsilyl)-5-(trifluoromethyl)-1H-indole

3-(2-azidoethyl)-2-(triethylsilyl)-5-(trifluoromethyl)-1H-indole wasprepared according to method D Step IV with3-(2-bromoethyl)-2-(triethylsilyl)-5-(trifluoromethyl)-1H-indole (0.448g; 1.10 mmol) and sodium azide (0.215 g; 3.31 mmol) in DMF (10 mL); theyield was 0.402 g (99%) of3-(2-azidoethyl)-2-(triethylsilyl)-5-(trifluoromethyl)-1H-indole as abrown oil.

ESI/APCI(+):391 (M+Na); ESI/APCI(−): 367 (M−H).

Intermediate 14—Preparation of2-(5-(trifluoromethyl)-1H-indol-3-yl)ethanamine

2-(5-(trifluoromethyl)-1H-indol-3-yl)ethanamine was prepared accordingto method D Step V with3-(2-azidoethyl)-2-(triethylsilyl)-5-(trifluoromethyl)-1H-indole (0.400g; 1.09 mmol) and triphenyl phosphine (0.427 g; 1.63 mmol) in methanol(5 mL) and tetrabutylamonium fluoride (3.26 mL, 1M) in THF (stirred for36 hours).

Intermediate 15—Preparation of 5-chloro-2-iodo-4-methylaniline

A solution of iodine (9.86 g; 38.84 mmol) and potassium iodide (6.45 g;38.84 mmol) in water was added dropwise to a suspension of3-chloro-4-methylaniline (5.00 g; 35.31 g) in a solution of sodiumbicarbonate (4.75 g; 56.50 mmol). The resulting mixture was stirred 72hours at room temperature filtrated and the solid dissolved indichloromethane, washed with a saturated solution of sodiumthiosulphate, dried over magnesium sulphate and concentrated underreduced pressure. The crude residue was purified by flash chromatographyon silica gel (eluent 2 to 20% ethyl acetate in heptane) to yield 2.30 g(24%) of 5-chloro-2-iodo-4-methylaniline as a brown solid.

ESI/APCI(+): 268 (M+H).

Intermediate 16—Preparation of2-(6-chloro-5-methyl-2-(triethylsilyl)-1H-indol-3-yl)ethanol

2-(6-chloro-5-methyl-2-(triethylsilyl)-1H-indol-3-yl)ethanol wasprepared according to method D Step II with5-chloro-2-iodo-4-methylaniline (1.50 g; 5.61 mmol),4-(triethylsilyl)but-3-yn-1-ol (2.36 mL; 11.22 mmol),Bis(diphenylphosphino)ferrocene]palladium(II) chloride (0.229 g; 0.280mmol), lithium chloride (0.237 g; 5.61 mmol) and sodium carbonate (1.19g; 11.22 mmol) in DMF (14 mL). The crude material was purified by flashchromatography on silica gel (eluent 2 to 20% ethyl acetate in heptane)to afford 1.44 g (79%) of2-(6-chloro-5-methyl-2-(triethylsilyl)-1H-indol-3-yl)ethanol as a brownoil.

ESI/APCI(+): 324 (M+H); ESI/APCI(−): 322 (M−H).

Intermediate 17—Preparation of3-(2-bromoethyl)-6-chloro-5-methyl-2-(triethylsilyl)-1H-indole

3-(2-bromoethyl)-6-chloro-5-methyl-2-(triethylsilyl)-1H-indole wasprepared according to method D Step III with2-(6-chloro-5-methyl-2-(triethylsilyl)-1H-indol-3-yl)ethanol (1.44 g;4.45 mmol) in THF (6 mL) and triphenyl phosphine (1.75 g; 6.67 mmol) andperbromomethane (2.21 g; 6.67 mmol) in THF (40 mL) pre-stirred for 30minutes. The crude mixture was purified by flash chromatography onsilica gel (eluent 2 to 20% ethyl acetate in heptane) to afford 0.725 g(42%) of 3-(2-bromoethyl)-6-chloro-5-methyl-2-(triethylsilyl)-1H-indoleas a brown oil.

Intermediate 18—Preparation of3-(2-azidoethyl)-6-chloro-5-methyl-2-(triethylsilyl)-1H-indole

3-(2-azidoethyl)-6-chloro-5-methyl-2-(triethylsilyl)-1H-indole wasprepared according to method D Step IV with3-(2-bromoethyl)-6-chloro-5-methyl-2-(triethylsilyl)-1H-indole (0.725 g;1.87 mmol) and sodium azide (0.365 g; 5.62 mmol) in DMF (8 mL); theyield was quantitative as a brown oil.

Intermediate 19—Preparation of2-(6-chloro-5-methyl-1H-indol-3-yl)ethanamine

2-(6-chloro-5-methyl-1H-indol-3-yl)ethanamine was prepared according tomethod D Step V with3-(2-azidoethyl)-6-chloro-5-methyl-2-(triethylsilyl)-1H-indole (0.654 g;1.87 mmol) and triphenylphosphine (0.737 g; 2.81 mmol) in methanol (10mL) and tetrabutylamonium fluoride (5.62 mL 1M) in THF (stirred for 36hours).

Intermediate 20—Preparation of 4,5-dichloro-2-iodoaniline

Iodine monochloride (1.39 mL; 27.77 mmol) was added to a solution of3,4-dichloroaniline (4.50 g; 27.77 mmol) in acetic acid (15 mL) and theresulting mixture was stirred 30 minutes at room temperature. Thesolution was concentrated to dryness, neutralized with sodiumbicarbonate and extracted with dichloromethane. The combined organiclayers were washed with a saturated solution of sodium thiosulphate,dried over magnesium sulphate and concentrated under reduced pressure.The crude material was purified by flash chromatography on silica gel(eluent 2 to 20% ethyl acetate in heptane) to afford 3.46 g (43%) of4,5-dichloro-2-iodoaniline as a brown solid.

¹H NMR (DMSO-d6) δ 7.73 (s, 1H); 6.91 (s, 1H), 5.63 (br s, 2H).

Intermediate 21—Preparation of2-(5,6-dichloro-2-(triethylsilyl)-1H-indol-3-yl)ethanol

2-(5,6-dichloro-2-(triethylsilyl)-1H-indol-3-yl)ethanol was preparedaccording to method D Step II with 4,5-dichloro-2-iodoaniline (1.50 g;5.21 mmol), 4-(triethylsilyl)but-3-yn-1-01 (1.65 mL; 7.81 mmol),Bis(diphenylphosphino)ferrocene]palladium(II) chloride (0.212 g; 0.260mmol), lithium chloride (0.221 g; 5.21 mmol) and sodium carbonate (1.10g; 10.42 mmol) in DMF (14 mL). The crude material was purified by flashchromatography on silica gel (eluent 2 to 20% ethyl acetate in heptane)to afford 1.44 g (79%) of2-(5,6-dichloro-2-(triethylsilyl)-1H-indol-3-yl)ethanol as a brown oil.

ESI/APCI(+):344 (M+H); ESI/APCI(−):342 (M−H).

Intermediate 22—Preparation of3-(2-bromoethyl)-5,6-dichloro-2-(triethylsilyl)-1H-indole

3-(2-bromoethyl)-5,6-dichloro-2-(triethylsilyl)-1H-indole was preparedaccording to method D Step III with2-(5,6-dichloro-2-(triethylsilyl)-1H-indol-3-yl)ethanol (1.7 g; 4.94mmol) in THF (6 mL) and triphenyl phosphine (2.59 g; 9.87 mmol) andperbromomethane (3.27 g; 9.87 mmol) in THF (40 mL) pre-stirred for 30minutes. The crude mixture was purified by flash chromatography onsilica gel (eluent 2 to 20% ethyl acetate in heptane) to yield 0.548 g(27%) of 3-(2-bromoethyl)-5,6-dichloro-2-(triethylsilyl)-1H-indole as abrown oil.

¹H NMR (DMSO-d₆) δ 10.90 (s, 1H); 7.88 (s, 1H); 7.56 (s, 1H); 3.61 (t,2H); 3.28 (t, 2H); 0.95 (m, 15H).

Intermediate 23—Preparation of3-(2-azidoethyl)-5,6-dichloro-2-(triethylsilyl)-1H-indole

3-(2-azidoethyl)-5,6-dichloro-2-(triethylsilyl)-1H-indole was preparedaccording to method D Step IV with3-(2-bromoethyl)-5,6-dichloro-2-(triethylsilyl)-1H-indole (0.548 g; 1.35mmol) and sodium azide (0.262 g; 4.04 mmol) in DMF (8 mL); the yield wasquantitative as a brown oil.

ESI/APCI(−): 367 (M−H).

Intermediate 24—Preparation of 2-(5,6-dichloro-1H-indol-3-yl)ethanamine

2-(5,6-dichloro-1H-indol-3-yl)ethanamine was prepared according tomethod D Step V with3-(2-azidoethyl)-5,6-dichloro-2-(triethylsilyl)-1H-indole (0.497 g; 1.35mmol) and triphenylphosphine (0.529 g; 1.35 mmol) in methanol (10 mL)and tetrabutylamonium fluoride (4.04 mL 1M) in THF (stirred for 36hours).

Intermediate 25—Preparation of 5-chloro-3-iodopyridin-2-amine

5-chloro-3-iodopyridin-2-amine was prepared according to method D Step Iwith Iodine (7.55 g; 29.73 mmol) was added to a mixture of5-chloropyridin-2-amine (3.00 g; 22.87 mmol) and silver sulphate (9.36g; 29.73 mmol) in ethanol (150 mL). The crude residue was purified byflash chromatography on silica gel (eluent 0 to 30% of ethyl acetate inheptane) to give 3.71 g (64%) of 5-chloro-3-iodopyridin-2-amine as abeige solid.

ESI/APCI(+): 255 (M+Na).

¹H NMR (CDCl3) □ 7.99 (d, 1H); 7.84 (d, 1H), 4.96 (s, 2H).

Intermediate 26—Preparation of2-(5-chloro-2-(triethylsilyl)-1H-pyrrolo[2,3-b]pyridin-3-yl)ethanol

2-(5-chloro-2-(triethylsilyl)-1H-pyrrolo[2,3-b]pyridin-3-yl)ethanol wasprepared according to method D Step II with5-chloro-3-iodopyridin-2-amine (2 g; 7.86 mmol),4-(triethylsilyl)but-3-yn-1-ol (4.35 g; 23.58 mmol);(1,1′-bis(diphenylphosphino)ferrocene)-dichloromethane (0.321 g; 0.393mmol), lithium chloride (0.333 g; 7.86 mmol) and sodium carbonate (1.67g; 15.72 mmol) in DMF (15 mL) for approximately 20 hours. The crudematerial was purified by flash chromatography on silica gel (eluent 2 to20% ethyl acetate in heptane) to afford 1.44 g (79%) of2-(5,6-dichloro-2-(triethylsilyl)-1H-indol-3-yl)ethanol as a brown oil.The crude material was purified by flash chromatography on silica gel(eluent 7 to 80% of ethyl acetate in heptane) to give 2.15 g (88%) of2-(5-chloro-2-(triethylsilyl)-1H-pyrrolo[2,3-b]pyridin-3-yl)ethanol as awhite solid.

ESI/APCI (+): 311 (M+H); ESI/APCI (−): 309 (M−H).

Intermediate 27—Preparation of3-(2-bromoethyl)-5-chloro-2-(triethylsilyl)-1H-pyrrolo[2,3-b]pyridine

3-(2-bromoethyl)-5-chloro-2-(triethylsilyl)-1H-pyrrolo[2,3-b]pyridinewas prepared according to method D Step III with2-(5-chloro-2-(triethylsilyl)-1H-pyrrolo[2,3-b]pyridin-3-yl)ethanol (2.0g; 6.43 mmol) in THF (30 mL) and triphenyl phosphine (2.56 g; 9.65 mmol)and perbromomethane (3.27 g, 9.65 mmol) in THF (40 mL) pre-stirred for30 minutes. The crude mixture was purified by flash chromatography onsilica gel (eluent 5 to 40% of ethyl acetate in heptanes) to yield 1.08g (45%) of3-(2-bromoethyl)-5-chloro-2-(triethylsilyl)-1H-pyrrolo[2,3-b]pyridine asa white solid.

¹H NMR (CDCl₃) □ 8.72 (s, 1H); 8.24 (d, 1H); 7.87 (d, 1H); 3.50 (t, 2H),3.31 (t, 2H) 1.01 (m, 9H); 0.93 (m, 6H).

Intermediate 28—Preparation of3-(2-azidoethyl)-5-chloro-2-(triethylsilyl)-1H-pyrrolo[2,3-b]pyridine

A mixture of3-(2-bromoethyl)-5-chloro-2-(triethylsilyl)-1H-pyrrolo[2,3-b]pyridine(1.05 g; 2.81 mmol) and sodium azide (0.547 g; 8.43 mmol) in DMF (8 mL)was stirred for 18 hours at 80° C. and was concentrated under reducedpressure. The residue was partitioned between water and dichloromethane.After separation, the dichloromethane solution was dried over magnesiumsulphate and was evaporated to give 0.943 g (100%) of3-(2-azidoethyl)-5-chloro-2-(triethylsilyl)-1H-pyrrolo[2,3-b]pyridine asa solid.

ESI/APCI(+): 336 (M+H); ESI/APCI(−): 334 (M−H).

Intermediate 29—Preparation of2-(5-chloro-2-(triethylsilyl)-1H-pyrrolo[2,3-b]pyridin-3-yl)ethanamine

A mixture of3-(2-azidoethyl)-5-chloro-2-(triethylsilyl)-1H-pyrrolo[2,3-b]pyridine(0.900 g; 2.68 mmol) and triphenylphosphine (1.05 g; 4.02 mmol) inmethanol (25 ml) was stirred at 80° C. for 1 hour and was concentratedunder reduced pressure. The residue was dissolved in toluene (15 mL).Hydrochloric acid (2 mL) and water 15 mL were added. After two layers'separation, the aqueous solution was extracted 3×15 mL of toluene andwas made alkaline by addition of a solution of sodium hydroxide 2N. Theformed precipitate was filtered off. The filtrate was extracted withdichloromethane (5×15 mL). Combined dichloromethane extracts were driedover magnesium sulphate and concentrated under reduced pressure to give0.515 g (62%) of2-(5-chloro-2-(triethylsilyl)-1H-pyrrolo[2,3-b]pyridin-3-yl)ethanamineas an oily residue.

ESI/APCI(+): 310 (M+H); 293 (M+H—NH₃); ESI/APCI(−): 308 (M−H).

Intermediate 30—Preparation of2-(5-chloro-1H-pyrrolo[2,3-b]pyridin-3-yl)ethanamine hydrochloride

2-(5-chloro-2-(triethylsilyl)-1H-pyrrolo[2,3-b]pyridin-3-yl)ethanamine(0.360 g; 1.16 mmol) was dissolved in a 1M solution oftetrabutylammonium fluoride in THF (4 mL; 4 mmol). The mixture wasstirred overnight at room temperature and was concentrated under reducedpressure. The residue was dissolved in dichloromethane. A 2M solution ofhydrogen chloride in ether was added and the formed precipitatecollected by filtration and dried under reduced pressure to give 0.239 g(89%) of 2-(5-chloro-1H-pyrrolo[2,3-b]pyridin-3-yl)ethanaminehydrochloride as a beige solid.

ESI/APCI(+): 196 (M+H), 179 (M+H—NH₃).

Intermediate 31—Preparation of 4-amino-3-iodobenzonitrile

4-amino-3-iodobenzonitrile was prepared according to method D Step Iwith Iodine (0.645 g; 2.54 mmol), silver sulphate (0.791 g; 2.54 mmol)and 4-aminobenzonitrile (0.300 g; 2.54 mmol) in ethanol (10 mL). Thecrude residue was purified by flash chromatography on silica gel (eluent2 to 40% ethyl acetate in heptane) to yield 0.222 g (36%) of4-amino-3-iodobenzonitrile as a white solid.

¹H NMR (DMSO-d₆) δ 7.96 (d, 1H), 7.45 (dd, 1H), 6.76 (d, 1H), 6.22 (s,2H).

Intermediate 32—Preparation of 1-(4-amino-3-iodophenyl)ethanone

1-(4-amino-3-iodophenyl)ethanone was prepared according to method D StepI with Iodine (2.82 g; 11.10 mmol) silver sulphate (3.46 g; 11.10 mmol)and 1-(4-aminophenyl)ethanone (1.50 g; 11.10 mmol) in ethanol (40 mL).The crude residue was purified by flash chromatography on silica gel(eluent 2 to 40% ethyl acetate in heptane) to yield 0.514 g (18%) of1-(4-amino-3-iodophenyl)ethanone as a pale yellow solid.

Intermediate 33—Preparation of 3,4,5-trifluoro-2-iodoaniline

3,4,5-trifluoro-2-iodoaniline was prepared according to method D Step Iwith iodine (0.621 g; 2.45 mmol), silver sulphate (0.763 g; 2.45 mmol)and 3,4,5-trifluoroaniline (0.360 g; 2.45 mmol) in ethanol (5 mL). Thecrude residue was purified by flash chromatography on silica gel (eluent2 to 40% ethyl acetate in heptane) to yield 0.279 g (42%) of3,4,5-trifluoro-2-iodoaniline as a white solid.

ESI/APCI(−): 272 (M−H).

Intermediate 34—Preparation of 3-(2-aminoethyl)-1H-indole-5-carbonitrile

3-(2-aminoethyl)-1H-indole-5-carbonitrile can be prepared according tomethod D step II, III, IV and V starting from4-amino-3-iodobenzonitrile.

Intermediate 35—Preparation of1-(3-(2-aminoethyl)-1H-indol-5-yl)ethanone

1-(3-(2-aminoethyl)-1H-indol-5-yl)ethanone can be prepared according tomethod D step II, III, IV and V starting from1-(4-amino-3-iodophenyl)ethanone.

Intermediate 36—Preparation of2-(4,5,6-trifluoro-1H-indol-3-yl)ethanamine

1-(3-(2-aminoethyl)-1H-indol-5-yl)ethanone can be prepared according tomethod D step II, III, IV and V starting from3,4,5-trifluoro-2-iodoaniline.

Examples of the Preparation of Compounds of the Invention Example 1Preparation ofN-(2-(5-chloro-1H-indol-3-yl)ethyl)-6-morpholinonicotinamide

N-(2-(5-chloro-1H-indol-3-yl)ethyl)-6-morpholinonicotinamide wasobtained following Method C starting from2-(5-chloro-1H-indol-3-yl)ethanamine hydrochloride (0.042 g, 0.178mmol), 6-morpholinonicotinoyl chloride (0.045 g; 0.178 mmol), andtriethylamine (0.062 mL; 0.446 mmol) in dichloromethane (5 mL). Flashchromatography on silica gel (eluent 1 to 10% methanol indichloromethane) furnished 0.039 g (57%) ofN-(2-(5-chloro-1H-indol-3-yl)ethyl)-6-morpholinonicotinamide as a solid.

ESI/APCI(+): 385 (M+H); ESI/APCI(−): 383 (M−H).

¹H NMR (DMSO-d₆) δ 11.03 (s, 1H), 8.61 (s, 1H), 8.41 (s, 1H), 7.97 (d,1H), 7.60 (s, 1H), 7.35 (d, 1H), 7.25 (s, 1H), 7.05 (d, 1H), 6.85 (d,1H), 3.69 (s, 4H), 3.50 (m, 6H), 2.90 (m, 2H).

Example 2 Preparation ofN-(2-(5-Fluoro-1H-indol-3-yl)ethyl)biphenyl-4-carboxamide

N-(2-(5-Fluoro-1H-indol-3-yl)ethyl)biphenyl-4-carboxamide was obtainedfollowing Method C starting from 2-(5-fluoro-1H-indol-3-yl)ethanamine(0.100 g, 0.561 mmol), biphenyl-4-carbonyl chloride (0.130 g; 0.589mmol), and triethylamine (0.095 mL; 0.673 mmol) in dichloromethane (5mL). Flash chromatography on silica gel (eluent 2 to 20% ethyl acetatein dichloromethane) furnished 0.152 g (76%) ofN-(2-(5-Fluoro-1H-indol-3-yl)ethyl)biphenyl-4-carboxamide as a whitesolid.

ESI/APCI(+): 359 (M+H), 381 (M+Na); ESI/APCI(−): 357 (M−H).

¹H NMR (DMSO-d₆) δ 10.94 (s, 1H); 8.68 (t, 1H); 7.75 (m, 4H); 7.50 (t,2H); 7.42 (d, 1H); 7.36 (m, 2H); 7.28 (d, 1H); 6.91 (td, 1H); 3.54 (q,2H); 2.94 (t, 2H).

Example 3 Preparation ofN-(2-(5-Methyl-1H-indol-3-yl)ethyl)biphenyl-4-carboxamide

N-(2-(5-Methyl-1H-indol-3-yl)ethyl)biphenyl-4-carboxamide was obtainedfollowing Method C starting from 2-(5-methyl-1H-indol-3-yl)ethanaminehydrochloride (0.080 g, 0.372 mmol), biphenyl-4-carbonyl chloride(0.0864 g; 0.391 mmol), and triethylamine (0.131 mL; 0.930 mmol) indichloromethane (5 mL). Flash chromatography on silica gel eluting with1 to 10% ethyl acetate in dichloromethane furnished 0.096 g (73%) ofN-(2-(5-Methyl-1H-indol-3-yl)ethyl)biphenyl-4-carboxamide as a whitesolid.

ESI/APCI(+): 355 (M+H), 377 (M+Na); ESI/APCI(−): 353 (M−H).

¹H NMR (DMSO-d₆) δ 10.68 (s, 1H); 8.66 (t, 1H); 7.95 (d, 2H); 7.75 (m,4H); 7.50 (t, 2H); 7.39 m, 2H); 7.22 (d, 1H); 7.14 (d, 1H); 6.88 (d,1H); 3.54 (q, 2H); 2.94 (t, 2H); 2.36 (s, 3H).

Example 4 Preparation ofN-(2-(5-Methoxy-1H-indol-3-yl)ethyl)biphenyl-4-carboxamide

N-(2-(5-Methoxy-1H-indol-3-yl)ethyl)biphenyl-4-carboxamide was obtainedfollowing Method C starting from 2-(5-methoxy-1H-indol-3-yl)ethanamine(0.100 g, 0.515 mmol), biphenyl-4-carbonyl chloride (0.120 g; 0.541mmol), and triethylamine (0.087 mL; 0.616 mmol) in dichloromethane (5mL). Flash chromatography on silica gel (eluent with 10% ethyl acetatein dichloromethane) furnished 0.122 g (64%) ofN-(2-(5-Methoxy-1H-indol-3-yl)ethyl)biphenyl-4-carboxamide as a whitesolid.

ESI/APCI(+): 371 (M+H); ESI/APCI(−): 369 (M−H).

Example 5 Preparation ofN-(2-(5-chloro-1H-Indo)-3-yl)ethyl)biphenyl-2-carboxamide

N-(2-(5-chloro-1H-Indo)-3-yl)ethyl)biphenyl-2-carboxamide was preparedfollowing Method A starting from 2-(5-chloro-1H-indol-3-yl)ethanaminehydrochloride (0.100 g; 0.424 mmol), biphenyl-2-carboxylic acid (0.0943g; 0.466 mmol), HATU (0.193 g; 0.508 mmol) and N,N-diisopropylethylamine(0.179 mL; 1.06 mmol) in DMF (5 mL). Flash chromatography on silica gel(eluent 1 to 10% ethyl acetate in dichloromethane) furnished 0.109 g(68%) of N-(2-(5-chloro-1H-Indo)-3-yl)ethyl)biphenyl-2-carboxamide as awhite solid.

ESI/APCI(+): 375 (M+H), 397 (M+Na); ESI/APCI(−): 373 (M−H).

Example 6 Preparation ofN-(2-(5-Chloro-1H-indol-3-yl)ethyl)biphenyl-3-carboxamide

N-(2-(5-Chloro-1H-indol-3-yl)ethyl)biphenyl-3-carboxamide was obtainedfollowing Method C starting from 2-(5-chloro-1H-indol-3-yl)ethanaminehydrochloride (0.100 g, 0.424 mmol), biphenyl-3-carbonyl chloride(0.0965 g; 0.445 mmol), and triethylamine (0.145 mL; 1.06 mmol) indichloromethane (5 mL). Flash chromatography on silica gel (eluent 2 to20% ethyl acetate in dichloromethane) furnished 0.0565 g (36%) ofN-(2-(5-Chloro-1H-indol-3-yl)ethyl)biphenyl-3-carboxamide as a whitesolid.

ESI/APCI(+): 375 (M+H), 397 (M+Na).

Example 7 Preparation ofN-(2-(5-Chloro-1H-indol-3-yl)ethyl)biphenyl-4-carboxamide

N-(2-(5-Chloro-1H-indol-3-yl)ethyl)biphenyl-4-carboxamide was obtainedfollowing Method C starting from 2-(5-chloro-1H-indol-3-yl)ethanaminehydrochloride (0.100 g, 0.424 mmol), biphenyl-4-carbonyl chloride (0.098g; 0.445 mmol), and triethylamine (0.131 mL; 0.934 mmol) indichloromethane (5 mL). Flash chromatography on silica gel (eluent 10%ethyl acetate in dichloromethane) furnished 0.125 g (79%) ofN-(2-(5-Chloro-1H-indol-3-yl)ethyl)biphenyl-4-carboxamide as a whitesolid.

ESI/APCI(+): 375 (M+H); ESI/APCI(−): 373 (M−H).

Example 8 Preparation ofN-(2-(5-Chloro-1H-indol-3-yl)ethyl)-4-(thiophen-2-yl)benzamide

N-(2-(5-Chloro-1H-indol-3-yl)ethyl)-4-(thiophen-2-yl)benzamide wasobtained following Method C starting from2-(5-chloro-1H-indol-3-yl)ethanamine hydrochloride (0.100 g, 0.424mmol), 4-(thiophen-2-yl)benzoyl chloride (0.102 g; 0.445 mmol), andtriethylamine (0.149 mL; 1.06 mmol) in dichloromethane (5 mL). Flashchromatography on silica gel (eluent 1 to 10% ethyl acetate indichloromethane) furnished 0.058 g (36%) ofN-(2-(5-Chloro-1H-indol-3-yl)ethyl)-4-(thiophen-2-yl)benzamide as awhite solid.

ESI/APCI(+): 381 (M+H); ESI/APCI(−): 379 (M−H).

Example 9 Preparation ofN-(2-(5-chloro-1H-indol-3-yl)ethyl)-2′-methoxybiphenyl-2-carboxamide

N-(2-(5-chloro-1H-indol-3-yl)ethyl)-2′-methoxybiphenyl-2-carboxamide wasprepared according to method B withN-(2-(5-chloro-1H-indol-3-yl)ethyl)-2-iodobenzamide (0.075 g; 0.176mmol), 2-methoxyphenylboronic acid (0.028 g; 0.180 mmol),tetrakis(triphenylphosphine)palladium (0.010 g; 0.009 mmol), sodiumcarbonate (0.037 g; 0.353 mmol), in dimethoxyethane (3 mL) and water (1mL), irradiated in a microwave oven at 130° C. for 15 minutes. Flashchromatography on silica gel (eluent 1 to 20% ethyl acetate indichloromethane) furnished 0.065 g (90%) ofN-(2-(5-chloro-1H-indol-3-yl)ethyl)-2′-methoxybiphenyl-2-carboxamide.

ESI/APCI(+): 405 (M+H), 427 (M+Na); ESI/APCI(−): 403 (M−H).

Example 10 Preparation ofN-(2-(5-chloro-1H-indol-3-yl)ethyl)-2′-methoxybiphenyl-3-carboxamide

N-(2-(5-chloro-1H-indol-3-yl)ethyl)-2′-methoxybiphenyl-3-carboxamide wasprepared according to method B withN-(2-(5-chloro-1H-indol-3-yl)ethyl)-3-iodobenzamide (0.075 g; 0.176mmol), 2-methoxyphenylboronic acid (0.028 g; 0.180 mmol),tetrakis(triphenylphosphine)palladium (0.010 g; 0.009 mmol), sodiumcarbonate (0.037 g; 0.353 mmol), in dimethoxyethane (3 mL) and water (1mL), irradiated in a microwave oven at 130° C. for 15 minutes. Flashchromatography on silica gel (eluent 1 to 20% ethyl acetate indichloromethane) furnished 0.056 g (78%) ofN-(2-(5-chloro-1H-indol-3-yl)ethyl)-2′-methoxybiphenyl-3-carboxamide asa white solid.

ESI/APCI(+): 405 (M+H), 427 (M+Na); ESI/APCI(−): 403 (M−H).

Example 11 Preparation ofN-(2-(5-chloro-1H-indol-3-yl)ethyl)-2′-methoxybiphenyl-4-carboxamide

N-(2-(5-chloro-1H-indol-3-yl)ethyl)-2′-methoxybiphenyl-4-carboxamide wasprepared according to method B withN-(2-(5-chloro-1H-indol-3-yl)ethyl)-4-iodobenzamide (0.075 g; 0.176mmol), 2-methoxyphenylboronic acid (0.028 g; 0.180 mmol),tetrakis(triphenylphosphine)palladium (0.010 g; 0.009 mmol), sodiumcarbonate (0.037 g; 0.353 mmol), in dimethoxyethane (3 mL) and water (1mL), irradiated in a microwave oven at 130° C. for 15 minutes. Flashchromatography on silica gel (eluent 1 to 20% ethyl acetate indichloromethane) furnished 0.062 g (87%) ofN-(2-(5-chloro-1H-indol-3-yl)ethyl)-2′-methoxybiphenyl-4-carboxamide.

ESI/APCI(+): 405 (M+H), 427 (M+Na); ESI/APCI(−): 403 (M−H).

Example 12 Preparation ofN-(2-(5-chloro-1H-indol-3-yl)ethyl)-3′-methoxybiphenyl-2-carboxamide

N-(2-(5-chloro-1H-indol-3-yl)ethyl)-3′-methoxybiphenyl-2-carboxamide wasprepared according to method B withN-(2-(5-chloro-1H-indol-3-yl)ethyl)-2-iodobenzamide (0.075 g; 0.176mmol), 3-methoxyphenylboronic acid (0.028 g; 0.180 mmol),tetrakis(triphenylphosphine)palladium (0.010 g; 0.009 mmol), sodiumcarbonate (0.037 g; 0.353 mmol), in dimethoxyethane (3 mL) and water (1mL), irradiated in a microwave oven at 130° C. for 15 minutes. Flashchromatography on silica gel (eluent 1 to 20% ethyl acetate indichloromethane) furnished 0.060 g (83%) ofN-(2-(5-chloro-1H-indol-3-yl)ethyl)-3′-methoxybiphenyl-2-carboxamide asa white solid.

ESI/APCI(+): 405 (M+H), 427 (M+Na); ESI/APCI(−): 403 (M−H).

Example 13 Preparation ofN-(2-(5-chloro-1H-indol-3-yl)ethyl)-3′-methoxybiphenyl-3-carboxamide

N-(2-(5-chloro-1H-indol-3-yl)ethyl)-3′-methoxybiphenyl-3-carboxamide wasprepared according to method B withN-(2-(5-chloro-1H-indol-3-yl)ethyl)-3-iodobenzamide (0.075 g; 0.176mmol), 3-methoxyphenylboronic acid (0.028 g; 0.180 mmol),tetrakis(triphenylphosphine)palladium (0.010 g; 0.009 mmol), sodiumcarbonate (0.037 g; 0.353 mmol), in dimethoxyethane (3 mL) and water (1mL), irradiated in a microwave oven at 130° C. for 15 minutes. Flashchromatography on silica gel (eluent 1 to 20% ethyl acetate indichloromethane) furnished 0.062 g (87%) ofN-(2-(5-chloro-1H-indol-3-yl)ethyl)-3′-methoxybiphenyl-3-carboxamide asa white solid.

ESI/APCI(+): 405 (M+H), 427 (M+Na); ESI/APCI(−): 403 (M−H).

Example 14 Preparation ofN-(2-(5-chloro-1H-indol-3-yl)ethyl)-3′-methoxybiphenyl-4-carboxamide

N-(2-(5-chloro-1H-indol-3-yl)ethyl)-3′-methoxybiphenyl-4-carboxamide wasprepared according to method B withN-(2-(5-chloro-1H-indol-3-yl)ethyl)-4-iodobenzamide (0.075 g; 0.176mmol), 3-methoxyphenylboronic acid (0.028 g; 0.180 mmol),tetrakis(triphenylphosphine)palladium (0.010 g; 0.009 mmol), sodiumcarbonate (0.037 g; 0.353 mmol), in dimethoxyethane (3 mL) and water (1mL), irradiated in a microwave oven at 130° C. for 15 minutes. Flashchromatography on silica gel (eluent 2 to 20% ethyl acetate indichloromethane) furnished 0.052 g (73%) ofN-(2-(5-chloro-1H-indol-3-yl)ethyl)-3′-methoxybiphenyl-4-carboxamide asa white solid.

ESI/APCI(+): 405 (M+H), 427 (M+Na); ESI/APCI(−): 403 (M−H).

Example 15 Preparation ofN-(2-(5-chloro-1H-indol-3-yl)ethyl)-4′-methoxybiphenyl-2-carboxamide

N-(2-(5-chloro-1H-indol-3-yl)ethyl)-4′-methoxybiphenyl-2-carboxamide wasprepared according to method B withN-(2-(5-chloro-1H-indol-3-yl)ethyl)-2-iodobenzamide (0.075 g; 0.176mmol), 4-methoxyphenylboronic acid (0.028 g; 0.180 mmol),tetrakis(triphenylphosphine)palladium (0.010 g; 0.009 mmol), sodiumcarbonate (0.037 g; 0.353 mmol), in dimethoxyethane (3 mL) and water (1mL), irradiated in a microwave oven at 130° C. for 15 minutes. Flashchromatography on silica gel (eluent 2 to 20% ethyl acetate indichloromethane) furnished 0.067 g (94%) ofN-(2-(5-chloro-1H-indol-3-yl)ethyl)-4′-methoxybiphenyl-2-carboxamide asa white solid.

ESI/APCI(+): 405 (M+H), 427 (M+Na); ESI/APCI(−): 403 (M−H).

Example 16 Preparation ofN-(2-(5-chloro-1H-indol-3-yl)ethyl)-4′-methoxybiphenyl-3-carboxamide

N-(2-(5-chloro-1H-indol-3-yl)ethyl)-4′-methoxybiphenyl-3-carboxamide wasprepared according to method B withN-(2-(5-chloro-1H-indol-3-yl)ethyl)-3-iodobenzamide (0.075 g; 0.176mmol), 4-methoxyphenylboronic acid (0.028 g; 0.180 mmol),tetrakis(triphenylphosphine)palladium (0.010 g; 0.009 mmol), sodiumcarbonate (0.037 g; 0.353 mmol), in dimethoxyethane (3 mL) and water (1mL), irradiated in a microwave oven at 130° C. for 15 minutes. Flashchromatography on silica gel (eluent 2 to 20% ethyl acetate indichloromethane) furnished 0.057 g (80%) ofN-(2-(5-chloro-1H-indol-3-yl)ethyl)-4′-methoxybiphenyl-3-carboxamide asa white solid.

ESI/APCI(+): 405 (M+H), 427 (M+Na); ESI/APCI(−): 403 (M−H).

Example 17 Preparation ofN-(2-(5-chloro-1H-indol-3-yl)ethyl)-4′-methoxybiphenyl-4-carboxamide

N-(2-(5-chloro-1H-indol-3-yl)ethyl)-4′-methoxybiphenyl-4-carboxamide wasprepared according to method B withN-(2-(5-chloro-1H-indol-3-yl)ethyl)-4-iodobenzamide (0.075 g; 0.176mmol), 4-methoxyphenylboronic acid (0.028 g; 0.180 mmol),tetrakis(triphenylphosphine)palladium (0.010 g; 0.009 mmol), sodiumcarbonate (0.037 g; 0.353 mmol), in dimethoxyethane (3 mL) and water (1mL), irradiated in a microwave oven at 130° C. for 15 minutes. Flashchromatography on silica gel (eluent 2 to 20% ethyl acetate indichloromethane) furnished 0.047 g (66%) ofN-(2-(5-chloro-1H-indol-3-yl)ethyl)-4′-methoxybiphenyl-4-carboxamide asa white solid.

ESI/APCI(+): 405 (M+H), 427 (M+Na); ESI/APCI(−): 403 (M−H).

Example 18 Preparation ofN-(2-(5-chloro-1H-indol-3-yl)ethyl)-2′-fluorobiphenyl-2-carboxamide

N-(2-(5-chloro-1H-indol-3-yl)ethyl)-2′-fluorobiphenyl-2-carboxamide wasprepared according to method B withN-(2-(5-chloro-1H-indol-3-yl)ethyl)-2-iodobenzamide (0.075 g; 0.176mmol), 2-fluorophenylboronic acid (0.026 g; 0.180 mmol),tetrakis(triphenylphosphine)palladium (0.010 g; 0.009 mmol), sodiumcarbonate (0.037 g; 0.353 mmol), in dimethoxyethane (3 mL) and water (1mL), irradiated in a microwave oven at 130° C. for 15 minutes. The crudematerial was purified by flash chromatography on silica gel (eluent 2 to20% ethyl acetate in dichloromethane) furnished 0.053 g (77%) ofN-(2-(5-chloro-1 H-indol-3-yl)ethyl)-2′-fluorobiphenyl-2-carboxamide asa white solid.

ESI/APCI(+): 393 (M+H), 415 (M+Na); ESI/APCI(−): 391 (M−H).

Example 19 Preparation ofN-(2-(5-chloro-1H-indol-3-yl)ethyl)-2′-fluorobiphenyl-3-carboxamide

N-(2-(5-chloro-1H-indol-3-yl)ethyl)-2′-fluorobiphenyl-3-carboxamide wasprepared according to method B withN-(2-(5-chloro-1H-indol-3-yl)ethyl)-3-iodobenzamide (0.075 g; 0.176mmol), 2-fluorophenylboronic acid (0.026 g; 0.180 mmol),tetrakis(triphenylphosphine)palladium (0.010 g; 0.009 mmol), sodiumcarbonate (0.037 g; 0.353 mmol), in dimethoxyethane (3 mL) and water (1mL), irradiated in a microwave oven at 130° C. for 15 minutes. Flashchromatography on silica gel (eluent 2 to 20% ethyl acetate indichloromethane) furnished 0.051 g (73%) ofN-(2-(5-chloro-1H-indol-3-yl)ethyl)-2′-fluorobiphenyl-3-carboxamide as awhite solid.

ESI/APCI(+): 393 (M+H), 415 (M+Na); ESI/APCI(−): 391 (M−H).

Example 20 Preparation ofN-(2-(5-chloro-1H-indol-3-yl)ethyl)-2′-fluorobiphenyl-4-carboxamide

N-(2-(5-chloro-1H-indol-3-yl)ethyl)-2′-fluorobiphenyl-4-carboxamide wasprepared according to method B withN-(2-(5-chloro-1H-indol-3-yl)ethyl)-4-iodobenzamide (0.075 g; 0.176mmol), 2-fluorophenylboronic acid (0.026 g; 0.180 mmol),tetrakis(triphenylphosphine)palladium (0.010 g; 0.009 mmol), sodiumcarbonate (0.037 g; 0.353 mmol), in dimethoxyethane (3 mL) and water (1mL), irradiated in a microwave oven at 130° C. for 15 minutes. Flashchromatography on silica gel (eluent 2 to 20% ethyl acetate indichloromethane) furnished 0.048 g (69%) ofN-(2-(5-chloro-1H-indol-3-yl)ethyl)-2′-fluorobiphenyl-4-carboxamide as awhite solid.

ESI/APCI(+): 393 (M+H), 415 (M+Na); ESI/APCI(−): 391 (M−H).

Example 21 Preparation ofN-(2-(5-chloro-1H-indol-3-yl)ethyl)-3′-fluorobiphenyl-2-carboxamide

N-(2-(5-chloro-1H-indol-3-yl)ethyl)-3′-fluorobiphenyl-2-carboxamide wasprepared according to method B withN-(2-(5-chloro-1H-indol-3-yl)ethyl)-2-iodobenzamide (0.075 g; 0.176mmol), 3-fluorophenylboronic acid (0.026 g; 0.180 mmol),tetrakis(triphenylphosphine)palladium (0.010 g; 0.009 mmol), sodiumcarbonate (0.037 g; 0.353 mmol), in dimethoxyethane (3 mL) and water (1mL), irradiated in a microwave oven at 130° C. for 15 minutes. Flashchromatography on silica gel (eluent 2 to 20% ethyl acetate indichloromethane) furnished 0.051 g (74%) ofN-(2-(5-chloro-1H-indol-3-yl)ethyl)-3′-fluorobiphenyl-2-carboxamide as awhite solid.

ESI/APCI(+): 393 (M+H), 415 (M+Na); ESI/APCI(−): 391 (M−H).

Example 22 Preparation ofN-(2-(5-chloro-1H-indol-3-yl)ethyl)-3′-fluorobiphenyl-3-carboxamide

N-(2-(5-chloro-1H-indol-3-yl)ethyl)-3′-fluorobiphenyl-3-carboxamide wasprepared according to method B withN-(2-(5-chloro-1H-indol-3-yl)ethyl)-3-iodobenzamide (0.075 g; 0.176mmol), 3-fluorophenylboronic acid (0.026 g; 0.180 mmol),tetrakis(triphenylphosphine)palladium (0.010 g; 0.009 mmol), sodiumcarbonate (0.037 g; 0.353 mmol), in dimethoxyethane (3 mL) and water (1mL), irradiated in a microwave oven at 130° C. for 15 minutes. Flashchromatography on silica gel (eluent 2 to 20% ethyl acetate indichloromethane) furnished 0.044 g (63%) ofN-(2-(5-chloro-1H-indol-3-yl)ethyl)-3′-fluorobiphenyl-3-carboxamide as awhite solid.

ESI/APCI(+): 393 (M+H); ESI/APCI(−): 391 (M−H).

Example 23 Preparation ofN-(2-(5-chloro-1H-indol-3-yl)ethyl)-3′-fluorobiphenyl-4-carboxamide

N-(2-(5-chloro-1H-indol-3-yl)ethyl)-3′-fluorobiphenyl-4-carboxamide wasprepared according to method B withN-(2-(5-chloro-1H-indol-3-yl)ethyl)-4-iodobenzamide (0.075 g; 0.176mmol), 3-fluorophenylboronic acid (0.026 g; 0.180 mmol),tetrakis(triphenylphosphine)palladium (0.010 g; 0.009 mmol), sodiumcarbonate (0.037 g; 0.353 mmol), in dimethoxyethane (3 mL) and water (1mL), irradiated in a microwave oven at 130° C. for 15 minutes. Flashchromatography on silica gel (eluent 2 to 20% ethyl acetate indichloromethane) furnished 0.059 g (85%) ofN-(2-(5-chloro-1H-indol-3-yl)ethyl)-3′-fluorobiphenyl-4-carboxamide as awhite solid.

ESI/APCI(+): 393 (M+H); ESI/APCI(−): 391 (M−H).

Example 24 Preparation ofN-(2-(5-chloro-1H-indol-3-yl)ethyl)-4′-fluorobiphenyl-2-carboxamide

N-(2-(5-chloro-1H-indol-3-yl)ethyl)-4′-fluorobiphenyl-2-carboxamide wasprepared according to method B withN-(2-(5-chloro-1H-indol-3-yl)ethyl)-2-iodobenzamide (0.075 g; 0.176mmol), 4-fluorophenylboronic acid (0.026 g; 0.180 mmol),tetrakis(triphenylphosphine)palladium (0.010 g; 0.009 mmol), sodiumcarbonate (0.037 g; 0.353 mmol), in dimethoxyethane (3 mL) and water (1mL), irradiated in a microwave oven at 130° C. for 15 minutes. Flashchromatography on silica gel (eluent 2 to 20% ethyl acetate indichloromethane) furnished 0.058 g (84%) ofN-(2-(5-chloro-1H-indol-3-yl)ethyl)-4′-fluorobiphenyl-2-carboxamide as awhite solid.

ESI/APCI(+): 393 (M+H), 415 (M+Na); ESI/APCI(−): 391 (M−H).

Example 25 Preparation ofN-(2-(5-chloro-1H-indol-3-yl)ethyl)-4′-fluorobiphenyl-3-carboxamide

N-(2-(5-chloro-1H-indol-3-yl)ethyl)-4′-fluorobiphenyl-2-carboxamide wasprepared according to method B withN-(2-(5-chloro-1H-indol-3-yl)ethyl)-3-iodobenzamide (0.075 g; 0.176mmol), 4-fluorophenylboronic acid (0.026 g; 0.180 mmol),tetrakis(triphenylphosphine)palladium (0.010 g; 0.009 mmol), sodiumcarbonate (0.037 g; 0.353 mmol), in dimethoxyethane (3 mL) and water (1mL), irradiated in a microwave oven at 130° C. for 15 minutes. Flashchromatography on silica gel (eluent 2 to 20% ethyl acetate indichloromethane) furnished 0.053 g (76%) ofN-(2-(5-chloro-1H-indol-3-yl)ethyl)-4′-fluorobiphenyl-3-carboxamide as awhite solid.

ESI/APCI(+): 393 (M+H), 415 (M+Na), 431 (M+K); ESI/APCI(−): 391 (M−H).

Example 26 Preparation ofN-(2-(5-chloro-1H-indol-3-yl)ethyl)-4′-fluorobiphenyl-4-carboxamide

N-(2-(5-chloro-1H-indol-3-yl)ethyl)-4′-fluorobiphenyl-4-carboxamide wasprepared according to method B withN-(2-(5-chloro-1H-indol-3-yl)ethyl)-4-iodobenzamide (0.075 g; 0.176mmol), 4-fluorophenylboronic acid (0.026 g; 0.180 mmol),tetrakis(triphenylphosphine)palladium (0.010 g; 0.009 mmol), sodiumcarbonate (0.037 g; 0.353 mmol), in dimethoxyethane (3 mL) and water (1mL), irradiated in a microwave oven at 130° C. for 15 minutes. Flashchromatography on silica gel (eluent 2 to 20% ethyl acetate indichloromethane) furnished 0.044 g (63%) ofN-(2-(5-chloro-1H-indol-3-yl)ethyl)-4′-fluorobiphenyl-4-carboxamide as awhite solid.

ESI/APCI(+): 393 (M+H), 415 (M+Na); ESI/APCI(−): 391 (M−H).

Example 27 Preparation ofN-(2-(5-chloro-1H-indol-3-yl)ethyl)-2′-cyanobiphenyl-3-carboxamide

N-(2-(5-chloro-1H-indol-3-yl)ethyl)-2′-cyanobiphenyl-3-carboxamide wasprepared according to method B withN-(2-(5-chloro-1H-indol-3-yl)ethyl)-3-iodobenzamide (0.075 g; 0.176mmol), 2-cyanophenylboronic acid (0.027 g; 0.180 mmol),tetrakis(triphenylphosphine)palladium (0.010 g; 0.009 mmol), sodiumcarbonate (0.037 g; 0.353 mmol), in dimethoxyethane (3 mL) and water (1mL), irradiated in a microwave oven at 130° C. for 15 minutes. Flashchromatography on silica gel (eluent 2 to 20% ethyl acetate indichloromethane) furnished 0.033 g (46%) ofN-(2-(5-chloro-1H-indol-3-yl)ethyl)-2′-cyanobiphenyl-3-carboxamide as awhite solid.

ESI/APCI(+): 400 (M+H), 422 (M+Na); ESI/APCI(−): 398 (M−H).

Example 28 Preparation ofN-(2-(5-chloro-1H-indol-3-yl)ethyl)-2′-cyanobiphenyl-4-carboxamide

N-(2-(5-chloro-1H-indol-3-yl)ethyl)-2′-cyanobiphenyl-4-carboxamide wasprepared according to method B withN-(2-(5-chloro-1H-indol-3-yl)ethyl)-4-iodobenzamide (0.075 g; 0.176mmol), 2-cyanophenylboronic acid (0.027 g; 0.180 mmol),tetrakis(triphenylphosphine)palladium (0.010 g; 0.009 mmol), sodiumcarbonate (0.037 g; 0.353 mmol), in dimethoxyethane (3 mL) and water (1mL), irradiated in a microwave oven at 130° C. for 15 minutes. Flashchromatography on silica gel (eluent 2 to 20% ethyl acetate indichloromethane) furnished 0.023 g (33%) ofN-(2-(5-chloro-1H-indol-3-yl)ethyl)-2′-cyanobiphenyl-4-carboxamide as awhite solid.

ESI/APCI(+): 400 (M+H), 422 (M+Na); ESI/APCI(−): 398 (M−H).

Example 29 Preparation ofN-(2-(5-chloro-1H-indol-3-yl)ethyl)-3′-cyanobiphenyl-2-carboxamide

N-(2-(5-chloro-1H-indol-3-yl)ethyl)-3′-cyanobiphenyl-2-carboxamide wasprepared according to method B withN-(2-(5-chloro-1H-indol-3-yl)ethyl)-2-iodobenzamide (0.075 g; 0.176mmol), 3-cyanophenylboronic acid (0.027 g; 0.180 mmol),tetrakis(triphenylphosphine)palladium (0.010 g; 0.009 mmol), sodiumcarbonate (0.037 g; 0.353 mmol), in dimethoxyethane (3 mL) and water (1mL), irradiated in a microwave oven at 130° C. for 15 minutes. Flashchromatography on silica gel (eluent 2 to 20% ethyl acetate indichloromethane) furnished 0.036 g (51%) ofN-(2-(5-chloro-1H-indol-3-yl)ethyl)-3′-cyanobiphenyl-2-carboxamide as awhite solid.

ESI/APCI(+): 400 (M+H), 422 (M+Na); ESI/APCI(−): 398 (M−H).

Example 30 Preparation ofN-(2-(5-chloro-1H-indol-3-yl)ethyl)-3′-cyanobiphenyl-3-carboxamide

N-(2-(5-chloro-1H-indol-3-yl)ethyl)-3′-cyanobiphenyl-3-carboxamide wasprepared according to method B withN-(2-(5-chloro-1H-indol-3-yl)ethyl)-3-iodobenzamide (0.075 g; 0.176mmol), 3-cyanophenylboronic acid (0.027 g; 0.180 mmol),tetrakis(triphenylphosphine)palladium (0.010 g; 0.009 mmol), sodiumcarbonate (0.037 g; 0.353 mmol), in dimethoxyethane (3 mL) and water (1mL), irradiated in a microwave oven at 130° C. for 15 minutes. Flashchromatography on silica gel (eluent 2 to 20% ethyl acetate indichloromethane) furnished 0.035 g (49%) ofN-(2-(5-chloro-1H-indol-3-yl)ethyl)-3′-cyanobiphenyl-3-carboxamidecompound as a white solid.

ESI/APCI(+): 400 (M+H), 422 (M+Na); ESI/APCI(−): 398 (M−H).

Example 31 Preparation ofN-(2-(5-chloro-1H-indol-3-yl)ethyl)-3′-cyanobiphenyl-4-carboxamide

N-(2-(5-chloro-1H-indol-3-yl)ethyl)-3′-cyanobiphenyl-4-carboxamide wasprepared according to method B withN-(2-(5-chloro-1H-indol-3-yl)ethyl)-4-iodobenzamide (0.075 g; 0.176mmol), 3-cyanophenylboronic acid (0.027 g; 0.180 mmol),tetrakis(triphenylphosphine)palladium (0.010 g; 0.009 mmol), sodiumcarbonate (0.037 g; 0.353 mmol), in dimethoxyethane (3 mL) and water (1mL), irradiated in a microwave oven at 130° C. for 15 minutes. Flashchromatography on silica gel (eluent 2 to 20% ethyl acetate indichloromethane) furnished 0.022 g (31%) ofN-(2-(5-chloro-1H-indol-3-yl)ethyl)-3′-cyanobiphenyl-4-carboxamide as awhite solid.

ESI/APCI(+):422 (M+Na); ESI/APCI(−): 398 (M−H).

Example 32 Preparation ofN-(2-(5-chloro-1H-indol-3-yl)ethyl)-4′-cyanobiphenyl-2-carboxamide

N-(2-(5-chloro-1H-indol-3-yl)ethyl)-4′-cyanobiphenyl-2-carboxamide wasprepared according to method B withN-(2-(5-chloro-1H-indol-3-yl)ethyl)-2-iodobenzamide (0.075 g; 0.176mmol), 4-cyanophenylboronic acid (0.027 g; 0.180 mmol),tetrakis(triphenylphosphine)palladium (0.010 g; 0.009 mmol), sodiumcarbonate (0.037 g; 0.353 mmol), in dimethoxyethane (3 mL) and water (1mL), irradiated in a microwave oven at 130° C. for 15 minutes. Flashchromatography on silica gel (eluent 2 to 20% ethyl acetate indichloromethane) furnished 0.032 g (46%) ofN-(2-(5-chloro-1H-indol-3-yl)ethyl)-4′-cyanobiphenyl-2-carboxamide as awhite solid.

ESI/APCI(+):422 (M+Na); ESI/APCI(−): 398 (M−H).

Example 33 Preparation ofN-(2-(5-chloro-1H-indol-3-yl)ethyl)-4′-cyanobiphenyl-3-carboxamide

N-(2-(5-chloro-1H-indol-3-yl)ethyl)-4′-cyanobiphenyl-3-carboxamide wasprepared according to method B withN-(2-(5-chloro-1H-indol-3-yl)ethyl)-3-iodobenzamide (0.075 g; 0.176mmol), 4-cyanophenylboronic acid (0.027 g; 0.180 mmol),tetrakis(triphenylphosphine)palladium (0.010 g; 0.009 mmol), sodiumcarbonate (0.037 g; 0.353 mmol), in dimethoxyethane (3 mL) and water (1mL), irradiated in a microwave oven at 130° C. for 15 minutes. Flashchromatography on silica gel (eluent 2 to 20% ethyl acetate indichloromethane) furnished 0.017 g (24%) ofN-(2-(5-chloro-1H-indol-3-yl)ethyl)-4′-cyanobiphenyl-3-carboxamide as awhite solid.

ESI/APCI(+): 400 (M+H), 422 (M+Na); ESI/APCI(−): 398 (M−H).

Example 34 Preparation ofN-(2-(5-chloro-1H-indol-3-yl)ethyl)-4′-cyanobiphenyl-4-carboxamide

N-(2-(5-chloro-1H-indol-3-yl)ethyl)-4′-cyanobiphenyl-4-carboxamide wasprepared according to method B withN-(2-(5-chloro-1H-indol-3-yl)ethyl)-4-iodobenzamide (0.075 g; 0.176mmol), 4-cyanophenylboronic acid (0.027 g; 0.180 mmol),tetrakis(triphenylphosphine)palladium (0.010 g; 0.009 mmol), sodiumcarbonate (0.037 g; 0.353 mmol), in dimethoxyethane (3 mL) and water (1mL), irradiated in a microwave oven at 130° C. for 15 minutes. Flashchromatography on silica gel (eluent 2 to 20% ethyl acetate indichloromethane) furnished 0.034 g (48%) ofN-(2-(5-chloro-1H-indol-3-yl)ethyl)-4′-cyanobiphenyl-4-carboxamide as awhite solid.

ESI/APCI(+): 400 (M+H), 422 (M+Na); ESI/APCI(−): 398 (M−H).

Example 35 Preparation of2′-chloro-N-(2-(5-chloro-1H-indol-3-yl)ethyl)biphenyl-2-carboxamide

2′-chloro-N-(2-(5-chloro-1H-indol-3-yl)ethyl)biphenyl-2-carboxamide wasprepared according to method B withN-(2-(5-chloro-1H-indol-3-yl)ethyl)-2-iodobenzamide (0.075 g; 0.176mmol), 2-chlorophenylboronic acid (0.029 g; 0.180 mmol),tetrakis(triphenylphosphine)palladium (0.010 g; 0.009 mmol), sodiumcarbonate (0.037 g; 0.353 mmol), in dimethoxyethane (3 mL) and water (1mL), irradiated in a microwave oven at 130° C. for 15 minutes. Flashchromatography on silica gel (eluent 10 to 80% ethyl acetate in heptane)furnished 0.043 g (60%) of2′-chloro-N-(2-(5-chloro-1H-indol-3-yl)ethyl)biphenyl-2-carboxamide as awhite solid.

ESI/APCI(+): 431 (M+Na); ESI/APCI(−): 407 (M−H).

Example 36 Preparation of2′-chloro-N-(2-(5-chloro-1H-indol-3-yl)ethyl)biphenyl-3-carboxamide

2′-chloro-N-(2-(5-chloro-1H-indol-3-yl)ethyl)biphenyl-3-carboxamide wasprepared according to method B withN-(2-(5-chloro-1H-indol-3-yl)ethyl)-3-iodobenzamide (0.075 g; 0.176mmol), 2-chlorophenylboronic acid (0.029 g; 0.180 mmol),tetrakis(triphenylphosphine)palladium (0.010 g; 0.009 mmol), sodiumcarbonate (0.037 g; 0.353 mmol), in dimethoxyethane (3 mL) and water (1mL), irradiated in a microwave oven at 130° C. for 15 minutes. Flashchromatography on silica gel (eluent 10 to 80% ethyl acetate in heptane)furnished 0.051 g (70%) of2′-chloro-N-(2-(5-chloro-1H-indol-3-yl)ethyl)biphenyl-3-carboxamide as awhite solid.

ESI/APCI(+): 431 (M+Na); ESI/APCI(−): 407 (M−H).

Example 37 Preparation of2′-chloro-N-(2-(5-chloro-1H-indol-3-yl)ethyl)biphenyl-4-carboxamide

2′-chloro-N-(2-(5-chloro-1H-indol-3-yl)ethyl)biphenyl-4-carboxamide wasprepared according to method B withN-(2-(5-chloro-1H-indol-3-yl)ethyl)-4-iodobenzamide (0.075 g; 0.176mmol), 2-chlorophenylboronic acid (0.029 g; 0.180 mmol),tetrakis(triphenylphosphine)palladium (0.010 g; 0.009 mmol), sodiumcarbonate (0.037 g; 0.353 mmol), in dimethoxyethane (3 mL) and water (1mL), irradiated in a microwave oven at 130° C. for 15 minutes. Flashchromatography on silica gel (eluent 10 to 80% ethyl acetate in heptane)furnished 0.060 g (82%) of2′-chloro-N-(2-(5-chloro-1H-indol-3-yl)ethyl)biphenyl-4-carboxamide as awhite solid.

ESI/APCI(+): 409 (M+H), 431 (M+Na); ESI/APCI(−): 407 (M−H).

Example 38 Preparation of3′-chloro-N-(2-(5-chloro-1H-indol-3-yl)ethyl)biphenyl-2-carboxamide

3′-chloro-N-(2-(5-chloro-1H-indol-3-yl)ethyl)biphenyl-2-carboxamide wasprepared according to method B withN-(2-(5-chloro-1H-indol-3-yl)ethyl)-2-iodobenzamide (0.075 g; 0.176mmol), 2-chlorophenylboronic acid (0.029 g; 0.180 mmol),tetrakis(triphenylphosphine)palladium (0.010 g; 0.009 mmol), sodiumcarbonate (0.037 g; 0.353 mmol), in dimethoxyethane (3 mL) and water (1mL), irradiated in a microwave oven at 130° C. for 15 minutes. Flashchromatography on silica gel (eluent 10 to 80% ethyl acetate in heptane)furnished 0.032 g (44%) of3′-chloro-N-(2-(5-chloro-1H-indol-3-yl)ethyl)biphenyl-2-carboxamide as awhite solid.

ESI/APCI(+):409 (M+H), 431 (M+Na); ESI/APCI(−): 407 (M−H).

Example 39 Preparation of3′-chloro-N-(2-(5-chloro-1H-indol-3-yl)ethyl)biphenyl-3-carboxamide

3′-chloro-N-(2-(5-chloro-1H-indol-3-yl)ethyl)biphenyl-3-carboxamide wasprepared according to method B withN-(2-(5-chloro-1H-indol-3-yl)ethyl)-3-iodobenzamide (0.075 g; 0.176mmol), 3-chlorophenylboronic acid (0.029 g; 0.180 mmol),tetrakis(triphenylphosphine)palladium (0.010 g; 0.009 mmol), sodiumcarbonate (0.037 g; 0.353 mmol), in dimethoxyethane (3 mL) and water (1mL), irradiated in a microwave oven at 130° C. for 15 minutes. Flashchromatography on silica gel (eluent 10 to 80% ethyl acetate in heptane)furnished 0.048 g (66%) of3′-chloro-N-(2-(5-chloro-1H-indol-3-yl)ethyl)biphenyl-3-carboxamide as awhite solid.

ESI/APCI(+): 409 (M+H), 431 (M+Na); ESI/APCI(−): 407 (M−H).

Example 40 Preparation of3′-chloro-N-(2-(5-chloro-1H-indol-3-yl)ethyl)biphenyl-4-carboxamide

3′-chloro-N-(2-(5-chloro-1H-indol-3-yl)ethyl)biphenyl-4-carboxamide wasprepared according to method B withN-(2-(5-chloro-1H-indol-3-yl)ethyl)-4-iodobenzamide (0.075 g; 0.176mmol), 3-chlorophenylboronic acid (0.029 g; 0.180 mmol),tetrakis(triphenylphosphine)palladium (0.010 g; 0.009 mmol), sodiumcarbonate (0.037 g; 0.353 mmol), in dimethoxyethane (3 mL) and water (1mL), irradiated in a microwave oven at 130° C. for 15 minutes. Flashchromatography on silica gel (eluent 10 to 80% ethyl acetate in heptane)furnished 0.047 g (65%) of3′-chloro-N-(2-(5-chloro-1H-indol-3-yl)ethyl)biphenyl-4-carboxamide as awhite solid.

ESI/APCI(+): 409 (M+H), 431 (M+Na); ESI/APCI(−): 407 (M−H).

Example 41 Preparation of4′-chloro-N-(2-(5-chloro-1H-indol-3-yl)ethyl)biphenyl-3-carboxamide

4′-chloro-N-(2-(5-chloro-1H-indol-3-yl)ethyl)biphenyl-3-carboxamide wasprepared according to method B withN-(2-(5-chloro-1H-indol-3-yl)ethyl)-3-iodobenzamide (0.075 g; 0.176mmol), 4-chlorophenylboronic acid (0.029 g; 0.180 mmol),tetrakis(triphenylphosphine)palladium (0.010 g; 0.009 mmol), sodiumcarbonate (0.037 g; 0.353 mmol), in dimethoxyethane (3 mL) and water (1mL), irradiated in a microwave oven at 130° C. for 15 minutes. Flashchromatography on silica gel (eluent 10 to 80% ethyl acetate in heptane)furnished 0.033 g (45%) of4′-chloro-N-(2-(5-chloro-1H-indol-3-yl)ethyl)biphenyl-3-carboxamide as awhite solid.

ESI/APCI(+): 409 (M+H).

Example 42 Preparation of4′-chloro-N-(2-(5-chloro-1H-indol-3-yl)ethyl)biphenyl-4-carboxamide

4′-chloro-N-(2-(5-chloro-1H-indol-3-yl)ethyl)biphenyl-4-carboxamide wasprepared according to method B withN-(2-(5-chloro-1H-indol-3-yl)ethyl)-4-iodobenzamide (0.075 g; 0.176mmol), 4-chlorophenylboronic acid (0.029 g; 0.180 mmol),tetrakis(triphenylphosphine)palladium (0.010 g; 0.009 mmol), sodiumcarbonate (0.037 g; 0.353 mmol), in dimethoxyethane (3 mL) and water (1mL), irradiated in a microwave oven at 130° C. for 15 minutes. Flashchromatography on silica gel (eluent 10 to 80% ethyl acetate in heptane)furnished 0.029 g (40%) of4′-chloro-N-(2-(5-chloro-1H-indol-3-yl)ethyl)biphenyl-4-carboxamide as awhite solid.

ESI/APCI(+): 409 (M+H).

Example 43 Preparation of4′-chloro-N-(2-(5-chloro-1H-indol-3-yl)ethyl)biphenyl-2-carboxamide

4′-chloro-N-(2-(5-chloro-1H-indol-3-yl)ethyl)biphenyl-2-carboxamide wasprepared according to method B withN-(2-(5-chloro-1H-indol-3-yl)ethyl)-2-iodobenzamide (0.075 g; 0.176mmol), 4-chlorophenylboronic acid (0.029 g; 0.180 mmol),tetrakis(triphenylphosphine)palladium (0.010 g; 0.009 mmol), sodiumcarbonate (0.037 g; 0.353 mmol), in dimethoxyethane (3 mL) and water (1mL), irradiated in a microwave oven at 180° C. for 5 minutes. Flashchromatography on silica gel (eluent 10 to 80% ethyl acetate in heptane)furnished 0.036 g (50%) of4′-chloro-N-(2-(5-chloro-1H-indol-3-yl)ethyl)biphenyl-2-carboxamide as awhite solid.

ESI/APCI(+): 431 (M+Na); ESI/APCI(−): 407 (M−H).

Example 44 Preparation ofN-(2-(5-chloro-1H-indol-3-yl)ethyl)-3′-(trifluoromethyl)biphenyl-2-carboxamide

N-(2-(5-chloro-1H-indol-3-yl)ethyl)-3′-(trifluoromethyl)biphenyl-2-carboxamidewas prepared according to method B withN-(2-(5-chloro-1H-indol-3-yl)ethyl)-2-iodobenzamide (0.075 g; 0.176mmol), 3-(trifluoromethyl)phenylboronic acid (0.035 g; 0.180 mmol),tetrakis(triphenylphosphine)palladium (0.010 g; 0.009 mmol), sodiumcarbonate (0.037 g; 0.353 mmol), in dimethoxyethane (3 mL) and water (1mL), irradiated in a microwave oven at 180° C. for 5 minutes. Flashchromatography on silica gel (eluent 10 to 80% ethyl acetate in heptane)furnished 0.047 g (60%) ofN-(2-(5-chloro-1H-indol-3-yl)ethyl)-3′-(trifluoromethyl)biphenyl-2-carboxamideas a white solid.

ESI/APCI(+): 443 (M+H) 465 (M+Na); ESI/APCI(−): 441 (M−H).

Example 45 Preparation ofN-(2-(5-chloro-1H-indol-3-yl)ethyl)-2′-(trifluoromethyl)biphenyl-4-carboxamide

N-(2-(5-chloro-1H-indol-3-yl)ethyl)-2′-(trifluoromethyl)biphenyl-4-carboxamidewas prepared according to method B withN-(2-(5-chloro-1H-indol-3-yl)ethyl)-4-iodobenzamide (0.075 g; 0.176mmol), 2-(trifluoromethyl)phenylboronic acid (0.035 g; 0.180 mmol),tetrakis(triphenylphosphine)palladium (0.010 g; 0.009 mmol), sodiumcarbonate (0.037 g; 0.353 mmol), in dimethoxyethane (3 mL) and water (1mL), irradiated in a microwave oven at 180° C. for 5 minutes. Flashchromatography on silica gel (eluent 10 to 80% ethyl acetate in heptane)furnished 0.031 g (40%) ofN-(2-(5-chloro-1H-indol-3-yl)ethyl)-2′-(trifluoromethyl)biphenyl-4-carboxamideas a white solid.

ESI/APCI(+): 443 (M+H); ESI/APCI(−): 441 (M−H).

Example 46 Preparation ofN-(2-(5-chloro-1H-indol-3-yl)ethyl)-2′-(trifluoromethyl)biphenyl-3-carboxamide

N-(2-(5-chloro-1H-indol-3-yl)ethyl)-3′-(trifluoromethyl)biphenyl-2-carboxamidewas prepared according to method B withN-(2-(5-chloro-1H-indol-3-yl)ethyl)-3-iodobenzamide (0.075 g; 0.176mmol), 2-(trifluoromethyl)phenylboronic acid (0.035 g; 0.180 mmol),tetrakis(triphenylphosphine)palladium (0.010 g; 0.009 mmol), sodiumcarbonate (0.037 g; 0.353 mmol), in dimethoxyethane (3 mL) and water (1mL), irradiated in a microwave oven at 180° C. for 5 minutes. Flashchromatography on silica gel (eluent 10 to 80% ethyl acetate in heptane)furnished 0.057 g (72%) ofN-(2-(5-chloro-1H-indol-3-yl)ethyl)-2′-(trifluoromethyl)biphenyl-3-carboxamideas a white solid.

ESI/APCI(+): 443 (M+H) 465 (M+Na); ESI/APCI(−): 441 (M−H).

Example 47 Preparation ofN-(2-(5-chloro-1H-indol-3-yl)ethyl)-3′-(trifluoromethyl)biphenyl-4-carboxamide

N-(2-(5-chloro-1H-indol-3-yl)ethyl)-3′-(trifluoromethyl)biphenyl-4-carboxamidewas prepared according to method B withN-(2-(5-chloro-1H-indol-3-yl)ethyl)-4-iodobenzamide (0.075 g; 0.176mmol), 3-(trifluoromethyl)phenylboronic acid (0.035 g; 0.180 mmol),tetrakis(triphenylphosphine)palladium (0.010 g; 0.009 mmol), sodiumcarbonate (0.037 g; 0.353 mmol), in dimethoxyethane (3 mL) and water (1mL), irradiated in a microwave oven at 180° C. for 5 minutes. Flashchromatography on silica gel (eluent 10 to 80% ethyl acetate in heptane)furnished 0.036 g (46%) ofN-(2-(5-chloro-1H-indol-3-yl)ethyl)-3′-(trifluoromethyl)biphenyl-4-carboxamideas a white solid.

ESI/APCI(+): 443 (M+H) 465 (M+Na); ESI/APCI(−): 441 (M−H).

Example 48 Preparation ofN-(2-(5-chloro-1H-indol-3-yl)ethyl)-4′-(trifluoromethyl)biphenyl-2-carboxamide

N-(2-(5-chloro-1H-indol-3-yl)ethyl)-4′-(trifluoromethyl)biphenyl-2-carboxamidewas prepared according to method B withN-(2-(5-chloro-1H-indol-3-yl)ethyl)-2-iodobenzamide (0.075 g; 0.176mmol), 4-(trifluoromethyl)phenylboronic acid (0.035 g; 0.180 mmol),tetrakis(triphenylphosphine)palladium (0.010 g; 0.009 mmol), sodiumcarbonate (0.037 g; 0.353 mmol), in dimethoxyethane (3 mL) and water (1mL), irradiated in a microwave oven at 180° C. for 5 minutes. Flashchromatography on silica gel (eluent 10 to 80% ethyl acetate in heptane)furnished 0.028 g (35%) ofN-(2-(5-chloro-1H-indol-3-yl)ethyl)-4′-(trifluoromethyl)biphenyl-2-carboxamideas a white solid.

ESI/APCI(+): 443 (M+H) 465 (M+Na); ESI/APCI(−): 441 (M−H).

Example 49 Preparation ofN-(2-(5-chloro-1H-indol-3-yl)ethyl)-4′-(trifluoromethyl)biphenyl-3-carboxamide

N-(2-(5-chloro-1H-indol-3-yl)ethyl)-4′-(trifluoromethyl)biphenyl-3-carboxamidewas prepared according to method B withN-(2-(5-chloro-1H-indol-3-yl)ethyl)-3-iodobenzamide (0.075 g; 0.176mmol), 4-(trifluoromethyl)phenylboronic acid (0.035 g; 0.180 mmol),tetrakis(triphenylphosphine)palladium (0.010 g; 0.009 mmol), sodiumcarbonate (0.037 g; 0.353 mmol), in dimethoxyethane (3 mL) and water (1mL), irradiated in a microwave oven at 180° C. for 5 minutes. Flashchromatography on silica gel (eluent 10 to 80% ethyl acetate in heptane)furnished 0.029 g (37%) ofN-(2-(5-chloro-1H-indol-3-yl)ethyl)-4′-(trifluoromethyl)biphenyl-3-carboxamideas a white solid.

ESI/APCI(+): 443 (M+H) 465 (M+Na); ESI/APCI(−): 441 (M−H).

Example 50 Preparation ofN-(2-(5-chloro-1H-indol-3-yl)ethyl)-3′-(trifluoromethyl)biphenyl-3-carboxamide

N-(2-(5-chloro-1H-indol-3-yl)ethyl)-4′-(trifluoromethyl)biphenyl-3-carboxamidewas prepared according to method B withN-(2-(5-chloro-1H-indol-3-yl)ethyl)-3-iodobenzamide (0.075 g; 0.176mmol), 3-(trifluoromethyl)phenylboronic acid (0.035 g; 0.180 mmol),tetrakis(triphenylphosphine)palladium (0.010 g; 0.009 mmol), sodiumcarbonate (0.037 g; 0.353 mmol), in dimethoxyethane (3 mL) and water (1mL), irradiated in a microwave oven at 130° C. for 15 minutes. Flashchromatography on silica gel (eluent 10 to 80% ethyl acetate in heptane)furnished 0.016 g (20%) ofN-(2-(5-chloro-1H-indol-3-yl)ethyl)-3′-(trifluoromethyl)biphenyl-3-carboxamideas a white solid.

ESI/APCI(+): 443 (M+H) 465 (M+Na); ESI/APCI(−): 441 (M−H).

Example 51 Preparation ofN-(2-(5-chloro-1H-indol-3-yl)ethyl)-4′-(trifluoromethyl)biphenyl-4-carboxamide

N-(2-(5-chloro-1H-indol-3-yl)ethyl)-4′-(trifluoromethyl)biphenyl-4-carboxamidewas prepared according to method B withN-(2-(5-chloro-1H-indol-3-yl)ethyl)-4-iodobenzamide (0.075 g; 0.176mmol), 4-(trifluoromethyl)phenylboronic acid (0.035 g; 0.180 mmol),tetrakis(triphenylphosphine)palladium (0.010 g; 0.009 mmol), sodiumcarbonate (0.037 g; 0.353 mmol), in dimethoxyethane (3 mL) and water (1mL), irradiated in a microwave oven at 130° C. for 15 minutes. Flashchromatography on silica gel (eluent 10 to 80% ethyl acetate in heptane)furnished 0.038 g (49%) ofN-(2-(5-chloro-1H-indol-3-yl)ethyl)-4′-(trifluoromethyl)biphenyl-4-carboxamideas a white solid.

ESI/APCI(+): 443 (M+H), 465 (M+Na); ESI/APCI(−): 441 (M−H).

Example 52 Preparation of N-(2-(5-chloro-1H-indol-3-yl)ethyl)-2′,6′-dimethylbiphenyl-3-carboxamide

N-(2-(5-chloro-1H-indol-3-yl)ethyl)-2′,6′-dimethylbiphenyl-3-carboxamidewas prepared according to method B withN-(2-(5-chloro-1H-indol-3-yl)ethyl)-3-iodobenzamide (0.075 g; 0.176mmol), 2,6-dimethyl phenylboronic acid (0.028 g; 0.180 mmol),tetrakis(triphenylphosphine)palladium (0.010 g; 0.009 mmol), sodiumcarbonate (0.037 g; 0.353 mmol), in dimethoxyethane (3 mL) and water (1mL), irradiated in a microwave oven at 130° C. for 15 minutes. Flashchromatography on silica gel (eluent 10 to 80% ethyl acetate in heptane)furnished 0.034 g (47%) ofN-(2-(5-chloro-1H-indol-3-yl)ethyl)-2′,6′-dimethylbiphenyl-3-carboxamideas a white solid.

ESI/APCI(+): 403 (M+H) 425 (M+Na); ESI/APCI(−): 401 (M−H).

Example 53 Preparation of N-(2-(5-chloro-1H-indol-3-yl)ethyl)-2′,6′-dimethylbiphenyl-4-carboxamide

N-(2-(5-chloro-1H-indol-3-yl)ethyl)-2′,6′-dimethylbiphenyl-4-carboxamidewas prepared according to method B withN-(2-(5-chloro-1H-indol-3-yl)ethyl)-4-iodobenzamide (0.075 g; 0.176mmol), 2,6-dimethyl phenylboronic acid (0.028 g; 0.180 mmol),tetrakis(triphenylphosphine)palladium (0.010 g; 0.009 mmol), sodiumcarbonate (0.037 g; 0.353 mmol), in dimethoxyethane (3 mL) and water (1mL), irradiated in a microwave oven at 130° C. for 15 minutes. Flashchromatography on silica gel (eluent 10 to 80% ethyl acetate in heptane)furnished 0.034 g (47%) ofN-(2-(5-chloro-1H-indol-3-yl)ethyl)-2′,6′-dimethylbiphenyl-4-carboxamideas a white solid.

ESI/APCI(+): 403 (M+H) 425 (M+Na); ESI/APCI(−): 401 (M−H).

Example 54 Preparation of N-(2-(5-chloro-1H-indol-3-yl)ethyl)-3′,4′-dimethylbiphenyl-2-carboxamide

N-(2-(5-chloro-1H-indol-3-yl)ethyl)-3′,4′-dimethylbiphenyl-2-carboxamidewas prepared according to method B withN-(2-(5-chloro-1H-indol-3-yl)ethyl)-2-iodobenzamide (0.075 g; 0.176mmol), 3,4-dimethyl phenylboronic acid (0.028 g; 0.180 mmol),tetrakis(triphenylphosphine)palladium (0.010 g; 0.009 mmol), sodiumcarbonate (0.037 g; 0.353 mmol), in dimethoxyethane (3 mL) and water (1mL), irradiated in a microwave oven at 130° C. for 15 minutes. Flashchromatography on silica gel (eluent 10 to 80% ethyl acetate in heptane)furnished 0.045 g (63%) ofN-(2-(5-chloro-1H-indol-3-yl)ethyl)-3′,4′-dimethylbiphenyl-2-carboxamideas a white solid.

ESI/APCI(+): 403 (M+H) 425 (M+Na).

Example 55 Preparation of N-(2-(5-chloro-1H-indol-3-yl)ethyl)-3′,4′-dimethylbiphenyl-3-carboxamide

N-(2-(5-chloro-1H-indol-3-yl)ethyl)-3′,4′-dimethylbiphenyl-3-carboxamidewas prepared according to method B withN-(2-(5-chloro-1H-indol-3-yl)ethyl)-3-iodobenzamide (0.075 g; 0.176mmol), 3,4-dimethyl phenylboronic acid (0.028 g; 0.180 mmol),tetrakis(triphenylphosphine)palladium (0.010 g; 0.009 mmol), sodiumcarbonate (0.037 g; 0.353 mmol), in dimethoxyethane (3 mL) and water (1mL), irradiated in a microwave oven at 130° C. for 15 minutes. Flashchromatography on silica gel (eluent 10 to 80% ethyl acetate in heptane)furnished 0.032 g (45%) ofN-(2-(5-chloro-1H-indol-3-yl)ethyl)-3′,4′-dimethylbiphenyl-3-carboxamideas a white solid.

ESI/APCI(+): 403 (M+H); ESI/APCI(−): 401 (M−H).

Example 56 Preparation of N-(2-(5-chloro-1H-indol-3-yl)ethyl)-3′,4′-dimethylbiphenyl-4-carboxamide

N-(2-(5-chloro-1H-indol-3-yl)ethyl)-3′,4′-dimethylbiphenyl-4-carboxamidewas prepared according to method B withN-(2-(5-chloro-1H-indol-3-yl)ethyl)-4-iodobenzamide (0.075 g; 0.176mmol), 3,4-dimethyl phenylboronic acid (0.028 g; 0.180 mmol),tetrakis(triphenylphosphine)palladium (0.010 g; 0.009 mmol), sodiumcarbonate (0.037 g; 0.353 mmol), in dimethoxyethane (3 mL) and water (1mL), irradiated in a microwave oven at 130° C. for 15 minutes. Flashchromatography on silica gel (eluent 10 to 80% ethyl acetate in heptane)furnished 0.048 g (68%) ofN-(2-(5-chloro-1H-indol-3-yl)ethyl)-3′,4′-dimethylbiphenyl-4-carboxamideas a white solid.

ESI/APCI(+): 403 (M+H); ESI/APCI(−): 401 (M−H).

Example 57 Preparation ofN-(2-(5-chloro-1H-indol-3-yl)ethyl)-2′-methylbiphenyl-2-carboxamide

N-(2-(5-chloro-1H-indol-3-yl)ethyl)-2′-methylbiphenyl-2-carboxamide wasprepared according to method B withN-(2-(5-chloro-1H-indol-3-yl)ethyl)-2-iodobenzamide (0.075 g; 0.176mmol), o-tolylboronic acid (0.025 g; 0.176 mmol),tetrakis(triphenylphosphine)palladium (0.010 g; 0.009 mmol), sodiumcarbonate (0.037 g; 0.353 mmol), in dimethoxyethane (3 mL) and water (1mL), irradiated in a microwave oven at 130° C. for 15 minutes. Flashchromatography on silica gel (eluent 2 to 10% ethyl acetate indichloromethane) furnished 0.043 g (63%) ofN-(2-(5-chloro-1H-indol-3-yl)ethyl)-2′-methylbiphenyl-2-carboxamide as awhite solid.

ESI/APCI(+): 389 (M+H); ESI/APCI(−): 387 (M−H).

Example 58 Preparation ofN-(2-(5-chloro-1H-indol-3-yl)ethyl)-2′-methylbiphenyl-3-carboxamide

N-(2-(5-chloro-1H-indol-3-yl)ethyl)-2′-methylbiphenyl-3-carboxamide wasprepared according to method B withN-(2-(5-chloro-1H-indol-3-yl)ethyl)-3-iodobenzamide (0.075 g; 0.176mmol), o-tolylboronic acid (0.025 g; 0.176 mmol),tetrakis(triphenylphosphine)palladium (0.010 g; 0.009 mmol), sodiumcarbonate (0.037 g; 0.353 mmol), in dimethoxyethane (3 mL) and water (1mL), irradiated in a microwave oven at 130° C. for 15 minutes. Flashchromatography on silica gel (eluent 2 to 10% ethyl acetate indichloromethane) furnished 0.054 g (79%) ofN-(2-(5-chloro-1H-indol-3-yl)ethyl)-2′-methylbiphenyl-3-carboxamide as awhite solid.

ESI/APCI(+): 389 (M+H); ESI/APCI(−): 387 (M−H).

¹H NMR (DMSO-d₆) δ 11.04 (s, 1H); 8.66 (t, 1H); 7.85 (m; 1H); 7.79 (brs, 1H), 7.60 (d, 1H); 7.56-7.48 (m, 2H); 7.36-7.22 (m, 6H); 7.05 (dd,1H); 3.51 (app q; 2H); 2.93 (t, 2H); 2.22 (s, 3H).

Example 59 Preparation ofN-(2-(5-chloro-1H-indol-3-yl)ethyl)-2′-methylbiphenyl-4-carboxamide

N-(2-(5-chloro-1H-indol-3-yl)ethyl)-2′-methylbiphenyl-4-carboxamide wasprepared according to method B withN-(2-(5-chloro-1H-indol-3-yl)ethyl)-4-iodobenzamide (0.075 g; 0.176mmol), o-tolylboronic acid (0.025 g; 0.176 mmol),tetrakis(triphenylphosphine)palladium (0.010 g; 0.009 mmol), sodiumcarbonate (0.037 g; 0.353 mmol), in dimethoxyethane (3 mL) and water (1mL), irradiated in a microwave oven at 130° C. for 15 minutes. Flashchromatography on silica gel (eluent 2 to 10% ethyl acetate indichloromethane) furnished 0.047 g (68%) ofN-(2-(5-chloro-1H-indol-3-yl)ethyl)-2′-methylbiphenyl-4-carboxamide as awhite solid.

ESI/APCI(+): 389 (M+H); ESI/APCI(−): 387 (M−H).

¹H NMR (DMSO-d₆) δ 11.05 (s, 1H); 8.67 (br s, 1H) 7.91 (d, 2H); 7.63 (s,1H); 7.44-7.05 (m, 8H); 7.06 (d, 1H); 3.55 (m, 2H); 2.95 (t; 2H); 2.42(s; 3H).

Example 60 Preparation ofN-(2-(5-chloro-1H-indol-3-yl)ethyl)-3′-methylbiphenyl-2-carboxamide

N-(2-(5-chloro-1H-indol-3-yl)ethyl)-3′-methylbiphenyl-2-carboxamide wasprepared according to method B withN-(2-(5-chloro-1H-indol-3-yl)ethyl)-2-iodobenzamide (0.075 g; 0.176mmol), m-tolylboronic acid (0.025 g; 0.176 mmol),tetrakis(triphenylphosphine)palladium (0.010 g; 0.009 mmol), sodiumcarbonate (0.037 g; 0.353 mmol), in dimethoxyethane (3 mL) and water (1mL), irradiated in a microwave oven at 130° C. for 15 minutes. Flashchromatography on silica gel (eluent 2 to 10% ethyl acetate indichloromethane) furnished 0.020 g (30%) ofN-(2-(5-chloro-1H-indol-3-yl)ethyl)-3′-methylbiphenyl-2-carboxamide as awhite solid.

ESI/APCI(+): 389 (M+H); ESI/APCI(−): 387 (M−H).

Example 61 Preparation ofN-(2-(5-chloro-1H-indol-3-yl)ethyl)-3′-methylbiphenyl-3-carboxamide

N-(2-(5-chloro-1H-indol-3-yl)ethyl)-3′-methylbiphenyl-3-carboxamide wasprepared according to method B withN-(2-(5-chloro-1H-indol-3-yl)ethyl)-3-iodobenzamide (0.075 g; 0.176mmol), m-tolylboronic acid (0.025 g; 0.176 mmol),tetrakis(triphenylphosphine)palladium (0.010 g; 0.009 mmol), sodiumcarbonate (0.037 g; 0.353 mmol), in dimethoxyethane (3 mL) and water (1mL), irradiated in a microwave oven at 130° C. for 15 minutes. Flashchromatography on silica gel (eluent 2 to 10% ethyl acetate indichloromethane) furnished 0.057 g (83%) ofN-(2-(5-chloro-1H-indol-3-yl)ethyl)-3′-methylbiphenyl-3-carboxamide as awhite solid.

ESI/APCI(+): 389 (M+H); ESI/APCI(−): 387 (M−H).

Example 62 Preparation ofN-(2-(5-chloro-1H-indol-3-yl)ethyl)-3′-methylbiphenyl-4-carboxamide

N-(2-(5-chloro-1H-indol-3-yl)ethyl)-3′-methylbiphenyl-4-carboxamide wasprepared according to method B withN-(2-(5-chloro-1H-indol-3-yl)ethyl)-4-iodobenzamide (0.075 g; 0.176mmol), m-tolylboronic acid (0.025 g; 0.176 mmol),tetrakis(triphenylphosphine)palladium (0.010 g; 0.009 mmol), sodiumcarbonate (0.037 g; 0.353 mmol), in dimethoxyethane (3 mL) and water (1mL), irradiated in a microwave oven at 130° C. for 15 minutes. Flashchromatography on silica gel (eluent 2 to 10% ethyl acetate indichloromethane) furnished 0.057 g (83%) ofN-(2-(5-chloro-1H-indol-3-yl)ethyl)-3′-methylbiphenyl-4-carboxamide as awhite solid.

ESI/APCI(+): 389 (M+H); ESI/APCI(−): 387 (M−H).

¹H NMR (DMSO-d₆) δ 11.05 (s, 1H); 8.67 (br s, 1H); 7.93 (d, 2H); 7.75(d, 2H); 7.64 (s, 1H); 7.53 (m, 2H); 7.38 (m, 2H); 7.29 (s, 1H); 7.23(d, 1H); 7.08 (d, 1H); 3.55 (m, 2H); 2.94 (t, 2H); 2.39 (s; 3H).

Example 63 Preparation ofN-(2-(5-chloro-1H-indol-3-yl)ethyl)-4′-methylbiphenyl-2-carboxamide

N-(2-(5-chloro-1H-indol-3-yl)ethyl)-4′-methylbiphenyl-2-carboxamide wasprepared according to method B withN-(2-(5-chloro-1H-indol-3-yl)ethyl)-2-iodobenzamide (0.075 g; 0.176mmol), p-tolylboronic acid (0.025 g; 0.176 mmol),tetrakis(triphenylphosphine)palladium (0.010 g; 0.009 mmol), sodiumcarbonate (0.037 g; 0.353 mmol), in dimethoxyethane (3 mL) and water (1mL), irradiated in a microwave oven at 130° C. for 15 minutes. Flashchromatography on silica gel (eluent 2 to 10% ethyl acetate indichloromethane) furnished 0.048 g (70%) ofN-(2-(5-chloro-1H-indol-3-yl)ethyl)-4′-methylbiphenyl-2-carboxamide as awhite solid.

ESI/APCI(+): 389 (M+H); ESI/APCI(−): 387 (M−H).

¹H NMR (DMSO-d₆) δ 11.03 (s, 1H); 8.25 (t, 1H); 7.52 (s, 1H); 7.50-7.44(m, 1H); 7.38-7.35 (m, 4H); 7.25 (d, 2H); 7.18 (s, 1H); 7.14-7.06 (m,3H); 3.35 (m, 2H); 2.71 (t, 2H); 1.99 (s, 3H).

Example 64 Preparation ofN-(2-(5-chloro-1H-indol-3-yl)ethyl)-4′-methylbiphenyl-3-carboxamide

N-(2-(5-chloro-1H-indol-3-yl)ethyl)-4′-methylbiphenyl-3-carboxamide wasprepared according to method B withN-(2-(5-chloro-1H-indol-3-yl)ethyl)-3-iodobenzamide (0.075 g; 0.176mmol), p-tolylboronic acid (0.025 g; 0.176 mmol),tetrakis(triphenylphosphine)palladium (0.010 g; 0.009 mmol), sodiumcarbonate (0.037 g; 0.353 mmol), in dimethoxyethane (3 mL) and water (1mL), irradiated in a microwave oven at 130° C. for 15 minutes. Flashchromatography on silica gel (eluent 2 to 10% ethyl acetate indichloromethane) furnished 0.056 g (82%) ofN-(2-(5-chloro-1H-indol-3-yl)ethyl)-4′-methylbiphenyl-3-carboxamide as awhite solid.

ESI/APCI(+): 389 (M+H); ESI/APCI(−): 387 (M−H).

Example 65 Preparation ofN-(2-(5-chloro-1H-indol-3-yl)ethyl)-4′-methylbiphenyl-4-carboxamide

N-(2-(5-chloro-1H-indol-3-yl)ethyl)-4′-methylbiphenyl-4-carboxamide wasprepared according to method B withN-(2-(5-chloro-1H-indol-3-yl)ethyl)-4-iodobenzamide (0.075 g; 0.176mmol), p-tolylboronic acid (0.025 g; 0.176 mmol),tetrakis(triphenylphosphine)palladium (0.010 g; 0.009 mmol), sodiumcarbonate (0.037 g; 0.353 mmol), in dimethoxyethane (3 mL) and water (1mL), irradiated in a microwave oven at 130° C. for 15 minutes. Flashchromatography on silica gel (eluent 2 to 10% ethyl acetate indichloromethane) furnished 0.051 g (74%) ofN-(2-(5-chloro-1H-indol-3-yl)ethyl)-4′-methylbiphenyl-4-carboxamide as awhite solid.

ESI/APCI(+): 389 (M+H); ESI/APCI(−): 387 (M−H).

Example 66 Preparation ofN-(2-(5-chloro-1H-indol-3-yl)ethyl)-4′-hydroxybiphenyl-2-carboxamide

N-(2-(5-chloro-1H-indol-3-yl)ethyl)-4′-hydroxybiphenyl-2-carboxamide wasprepared according to method B withN-(2-(5-chloro-1H-indol-3-yl)ethyl)-2-iodobenzamide (0.075 g; 0.176mmol), 4-hydroxyphenylboronic acid (0.024 g; 0.177 mmol),tetrakis(triphenylphosphine)palladium (0.010 g; 0.009 mmol), sodiumcarbonate (0.037 g; 0.353 mmol), in dimethoxyethane (3 mL) and water (1mL), irradiated in a microwave oven at 130° C. for 18 minutes. Flashchromatography on silica gel (eluent 10 to 80% ethyl acetate in heptane)furnished 0.017 g (26%) ofN-(2-(5-chloro-1H-indol-3-yl)ethyl)-4′-hydroxybiphenyl-2-carboxamide asa white solid.

ESI/APCI(+): 391 (M+H); ESI/APCI(−): 389 (M−H).

¹H NMR (DMSO-d₆) δ 11.04 (s, 1H); 9.48 (s, 1H); 8.18 (t, 1H); 7.56-71(m, 2H); 7.44 (m, 1H), 7.35 (m, 3H); 7.21 (m, 3H); 7.07 (d, 1H); 6.77(d, 2H); 3.34 (m, 2H); 2.72 (m, 2H).

Example 67 Preparation ofN-(2-(5-chloro-1H-indol-3-yl)ethyl)-4′-hydroxybiphenyl-3-carboxamide

N-(2-(5-chloro-1H-indol-3-yl)ethyl)-4′-hydroxybiphenyl-3-carboxamide wasprepared according to method B withN-(2-(5-chloro-1H-indol-3-yl)ethyl)-3-iodobenzamide (0.075 g; 0.176mmol), 4-hydroxyphenylboronic acid (0.024 g; 0.177 mmol),tetrakis(triphenylphosphine)palladium (0.010 g; 0.009 mmol), sodiumcarbonate (0.037 g; 0.353 mmol), in dimethoxyethane (3 mL) and water (1mL), irradiated in a microwave oven at 130° C. for 18 minutes. Flashchromatography on silica gel (eluent 10 to 80% ethyl acetate in heptane)furnished 0.010 g (14%) ofN-(2-(5-chloro-1H-indol-3-yl)ethyl)-4′-hydroxybiphenyl-3-carboxamide asa white solid.

ESI/APCI(+): 391 (M+H); ESI/APCI(−): 389 (M−H).

¹H NMR (DMSO-d₆) δ 11.06 (s, 1H); 9.65 (s, 1H); 8.70 (t, 1H); 8.02 (s,1H); 7.74 (t, 2H); 7.64 (s, 1H); 7.47-7.57 (m, 3H), 7.37 (d, 1H); 7.29(s, 1H); 7.07 (d, 1H); 6.88 (d, 2H); 3.54 (m, 2H); 2.96 (m, 2H).

Example 68 Preparation ofN-(2-(5-chloro-1H-indol-3-yl)ethyl)-4′-hydroxybiphenyl-4-carboxamide

N-(2-(5-chloro-1H-indol-3-yl)ethyl)-4′-hydroxybiphenyl-4-carboxamide wasprepared according to method B withN-(2-(5-chloro-1H-indol-3-yl)ethyl)-4-iodobenzamide (0.075 g; 0.176mmol), 4-hydroxyphenylboronic acid (0.024 g; 0.177 mmol),tetrakis(triphenylphosphine)palladium (0.010 g; 0.009 mmol), sodiumcarbonate (0.037 g; 0.353 mmol), in dimethoxyethane (3 mL) and water (1mL), irradiated in a microwave oven at 130° C. for 18 minutes. Flashchromatography on silica gel (eluent 10 to 80% ethyl acetate in heptane)furnished 0.017 g (26%) ofN-(2-(5-chloro-1H-indol-3-yl)ethyl)-4′-hydroxybiphenyl-4-carboxamide asa white solid.

ESI/APCI(+): 391 (M+H); ESI/APCI(−): 389 (M−H).

¹H NMR (DMSO-d₆) δ 11.04 (s, 1H); 9.68 (s, 1H); 8.61 (t, 1H); 7.87 (d,2H); 7.65 (m, 3H); 7.57 (d, 2H); 7.35 (d, 1H); 7.29 (s, 1H); 7.05 (d,1H); 6.86 (d, 2H); 3.52 (m, 2H); 2.93 (m, 2H).

Example 69 Preparation ofN-(2-(5-chloro-1H-indol-3-yl)ethyl)-3-(pyridin-4-yl)benzamide

N-(2-(5-chloro-1H-indol-3-yl)ethyl)-3-(pyridin-4-yl)benzamide wasprepared according to method B withN-(2-(5-chloro-1H-indol-3-yl)ethyl)-3-iodobenzamide (0.075 g; 0.176mmol), pyridin-4-ylboronic acid (0.025 g; 0.177 mmol),tetrakis(triphenylphosphine)palladium (0.010 g; 0.009 mmol), sodiumcarbonate (0.037 g; 0.353 mmol), in dimethoxyethane (3 mL) and water (1mL), irradiated in a microwave oven at 130° C. for 18 minutes. Flashchromatography on silica gel (eluent 10 to 80% ethyl acetate in heptane)furnished 0.047 g (71%) ofN-(2-(5-chloro-1H-indol-3-yl)ethyl)-3-(pyridin-4-yl)benzamide as a whitesolid.

ESI/APCI(+): 376 (M+H); ESI/APCI(−): 374 (M−H).

¹H NMR (DMSO-d₆) δ 11.05 (s, 1H); 8.78 (m, 1H); 8.68 (m, 2H); 8.21 (s,1H); 7.95 (t, 2H); 7.76 (m, 2H); 7.64 (m, 2H); 7.35 (d, 1H); 7.29 (s,1H); 7.05 (d, 1H); 3.55 (m, 2H); 2.96 (m, 2H).

Example 70 Preparation ofN-(2-(5-chloro-1H-indol-3-yl)ethyl)-4-(pyridin-4-yl)benzamide

N-(2-(5-chloro-1H-indol-3-yl)ethyl)-4-(pyridin-4-yl)benzamide wasprepared according to method B withN-(2-(5-chloro-1H-indol-3-yl)ethyl)-4-iodobenzamide (0.075 g; 0.176mmol), pyridin-4-ylboronic acid (0.025 g; 0.177 mmol),tetrakis(triphenylphosphine)palladium (0.010 g; 0.009 mmol), sodiumcarbonate (0.037 g; 0.353 mmol), in dimethoxyethane (3 mL) and water (1mL), irradiated in a microwave oven at 130° C. for 18 minutes. Flashchromatography on silica gel (eluent 10 to 80% ethyl acetate in heptane)furnished 0.051 g (77%) ofN-(2-(5-chloro-1H-indol-3-yl)ethyl)-4-(pyridin-4-yl)benzamide as a whitesolid.

ESI/APCI(+): 376 (M+H); ESI/APCI(−): 374 (M−H).

¹H NMR (DMSO-d₆) δ 11.06 (s, 1H); 8.74 (m, 1H); 8.69 (m, 2H); 7.98 (m,4H); 7.80 (m, 2H); 7.64 (s, 1H); 7.37 (d, 1H); 7.29 (s, 1H); 7.05 (d,1H); 3.54 (m, 2H); 2.96 (m, 2H).

Example 71 PreparationN-(2-(5-Chloro-1H-indol-3-yl)ethyl)-2-(1H-pyrazol-1-yl)benzamide

A mixture of N-(2-(5-chloro-1H-indol-3-yl)ethyl)-2-iodobenzamide (0.080g; 0.188 mmol), 1H-pyrazole (0.065 g; 0.942 mmol), copper (I) iodide(0.0036 g; 0.002 mmol), and potassium carbonate (0.032 g; 0.226 mmol) in2-propanol (3 ml) was irradiated in a microwave oven microwave for 20minutes at 150° C. The volatiles were removed under reduced pressure andthe residue was partitioned between water and ethyl acetate. The aqueouslayer was then extracted several times with ethyl acetate. The combinedorganic layers were evaporated to dryness and the residue was purifiedby flash chromatography on silica gel (eluent 1 to 10% methanol indichloromethane) to afford 0.028 g (41%) ofN-(2-(5-Chloro-1H-indol-3-yl)ethyl)-2-(1H-pyrazol-1-yl)benzamide as awhite solid.

ESI/APCI(+): 365 (M+H); ESI/APCI(−): 363 (M−H).

Example 72 Preparation ofN-(2-(5-chloro-1H-indol-3-yl)ethyl)-6-phenylpyridazine-3-carboxamide

A mixture of phenylboronic acid (0.022 g; 0.179 mmol),6-chloro-N-(2-(5-chloro-1H-indol-3-yl)ethyl)pyridazine-3-carboxamide(0.050 g; 0.149 mmol),[1,1′-Bis(diphenylphosphino)ferrocene]palladium(II) chloride (0.012 g;0.015 mmol), sodium iodide (0.044 g; 0.298 mmol) and sodium carbonate(0.032 g; 0.298 mmol) in dimethoxyethane (3 mL) and water (1 mL) wasirradiated in the microwave oven at 130° C. for 15 minutes. Theresulting solution was reported between water and ethyl acetate and theorganic layer was concentrated under reduced pressure. The crudematerial was purified by flash chromatography on silica gel (eluent 20to 80% ethyl acetate in heptane) to afford 0.0038 g (7%) ofN-(2-(5-chloro-1H-indol-3-yl)ethyl)-6-phenylpyridazine-3-carboxamide asa white solid.

ESI/APCI(+): 377 (M+H); ESI/APCI(−): 375 (M−H).

It is known to the skilled in the art that many additional compounds ofthe invention can be prepared with the same procedures as describedherein. Additional examples of such other compounds of present inventioninclude:2-(1H-pyrazol-1-yl)-N-(2-(5-(trifluoromethyl)-1H-indol-3-yl)ethyl)benzamide;3-(pyridin-3-yl)-N-(2-(5-(trifluoromethyl)-1H-indol-3-yl)ethyl)benzamide;4-(furan-2-yl)-N-(2-(5-(trifluoromethyl)-1 H-indol-3-yl)ethyl)benzamide;N-(2-(5-cyano-1H-indol-3-yl)ethyl)-3′-fluorobiphenyl-2-carboxamide;N-(2-(5-cyano-1H-indol-3-yl)ethyl)-3-(1H-imidazol-5-yl)benzamide;N-(2-(5-cyano-1H-indol-3-yl)ethyl)-4-(thiophen-3-yl)benzamide;N-(2-(5,6-dichloro-1H-indol-3-yl)ethyl)-2-(1H-pyrazol-1-yl)benzamide;N-(2-(5,6-dichloro-1H-indol-3-yl)ethyl)-2′-methylbiphenyl-3-carboxamide;N-(2-(5,6-dichloro-1H-indol-3-yl)ethyl)-4-(pyridin-4-yl)benzamide;3′-chloro-N-(2-(6-chloro-5-methyl-1H-indol-3-yl)ethyl)biphenyl-2-carboxamide;N-(2-(6-chloro-5-methyl-1H-indol-3-yl)ethyl)-2′-cyanobiphenyl-3-carboxamide;N-(2-(6-chloro-5-methyl-1H-indol-3-yl)ethyl)-4-(pyridin-2-yl)benzamide;N-(2-(5-acetyl-1H-indol-3-yl)ethyl)-2-(oxazol-5-yl)benzamide;N-(2-(5-acetyl-1H-indol-3-yl)ethyl)-4′-hydroxybiphenyl-3-carboxamide;N-(2-(5-acetyl-1H-indol-3-yl)ethyl)-2′-chlorobiphenyl-4-carboxamide;N-(2-(5-chloro-1H-pyrrolo[2,3-b]pyridin-3-yl)ethyl)-2-(oxazol-2-yl)benzamide;N-(2-(5-chloro-1H-pyrrolo[2,3-b]pyridin-3-yl)ethyl)-3′-hydroxybiphenyl-3-carboxamide;N-(2-(5-chloro-1H-pyrrolo[2,3-b]pyridin-3-yl)ethyl)-4-(thiophen-2-yl)benzamide;N-(2-(5-chloro-1H-indol-3-yl)ethyl)-2-(thiophen-3-yl)benzamide;N-(2-(5-chloro-1H-indol-3-yl)ethyl)-3-(pyridin-2-yl)benzamide;N-(2-(5-chloro-1H-indol-3-yl)ethyl)-4-(oxazol-2-yl)benzamide;N-(2-(5-chloro-1H-indol-3-yl)ethyl)-6-(pyridin-3-yl)pyridazine-3-carboxamide;N-(2-(6-chloro-5-methyl-1H-indol-3-yl)ethyl)-6-(1-methyl-1H-pyrazol-4-yl)pyridazine-3-carboxamide;N-((5-chloro-1H-indol-3-yl)methyl)-3′-fluorobiphenyl-3-carboxamide;N-((5-chloro-1H-indol-3-yl)methyl)-4-(oxazol-5-yl)benzamide;N-((5-chloro-1H-indol-3-yl)methyl)-6-(pyridin-4-yl)pyridazine-3-carboxamide;N-(3-(5-chloro-1H-indol-3-yl)propyl)-2-(1H-pyrazol-1-yl)benzamide;N-(3-(5-chloro-1H-indol-3-yl)propyl)-3′-fluorobiphenyl-3-carboxamide;N-(3-(5-chloro-1H-indol-3-yl)propyl)-4-(oxazol-2-yl)benzamide.

Part B Example 73 Construction of a TAU Gene Over-Expressing Cell Line

A TAU expression plasmid was constructed by sub-cloning the cDNA ofhuman TAU-P301L (encoding for TAU with proline 301 substituted by aleucine residue) into mammalian expression vector pcDNA3.1 resulting inplasmid pcDNA3.1-TAU P301L. Plasmids pcDNA3.1 and pcDNA3.1-TAU P301Lwere transfected to human neuroblastoma cells (BM17; ATCC No. CRL-2267)and independent clonal lines with the plasmids stably integrated intothe genome were selected. These resulted in cell lines named M17-3.1 andM17-TAU(P301L) (transfected with pcDNA3.1 and pcDNA3.1-TAU P301L,respectively). Expression of the TAU P301L genes in the cell lines wasconfirmed by Western analysis.

Example 74 Use of TAU Expressing Cells as a Model of NeuronalDegradation

The expression of TAU P301L in M17-TAU(P301L) cells was found to conferincreased toxicity relative to control cells expressing wild type TAU(M17-TAUwt). In degenerated or dead cells lactate dehydrogenase (LDH) isleaked out of the cells into the extracellular environment due to a lossof plasma-membrane integrity. This principle was used to determinecytotoxicity by quantifying the level of leaked LDH into the growthmedium.

The detailed method for determining TAU cytotoxicity was as follows:From appropriate precultures of M17-3.1 and M17-TAU(P301L) cells wereseeded at 2500 cells/cm2 in Optimem Reduced Serum without phenol red(Gibco, Cat. 31985-047) supplemented with 1% fetal calf serum, 1 mMsodium pyruvate, 1×non-essential amino acids, 500 μg/ml G4180.5×antibiotic/antimycotic. After 3 h of incubation at 37° C./5% CO2 1volume of Optimem Reduced Serum (same as described above; except withoutfetal calf serum) supplemented with 2.5 μM retinoic acid (RA) was added.The cells were further incubated for 7 days. Subsequently, LDH activitywas determined using Promega Cytotox 96 Non-Radioactive cytotoxicityassay, (Cat. G1780) according the supplier's instructions. FIG. 1 showsthat of M17-TAU P301L cells, but not of M17-3.1 cells display arelatively high level of LDH leaked into the medium demonstratingtoxicity specifically provoked by TAU P301.

Example 75 Use of the TAU Expressing Cells for the Testing of ExemplaryCompounds of this Invention

The M17-TAU P301L cell line made it possible to assess the ability ofnovel compounds to counteract TAU cytotoxicity. Active inhibitors of TAUcytotoxicity were found to inhibit LDH leakage of M17-TAU P301L cellstreated as described in Example 75 Efficacy (potency) of the compoundswas determined by testing compounds at different concentrations rangingfrom non-effective (thus at a relatively low concentration) to aneffective concentration for their ability to reduce LDH activity ofretinoic acid incubated M17-TAU P301L cells. These measurements wereused to calculate EC50 values of table 2.

Example 76 In-Vivo Inhibition of Pathological TAU-Phosphorylation

Human TAU R406W transgenic mice (Zhang et al, J. of Neuroscience24(19):4657-4667, 2004) are treated once-a-day subcutaneously for 4weeks with a compound of the invention (for example see table 1)dissolved in a formulation such as arachidin oil at a dose of forexample 35 mg/kg. Correspondingly vehicle treated transgenics areincluded as controls. At the end of the treatment period mice aresacrificed and brainstem is stereotactically collected. Soluble proteinfractions are prepared (Terwel et al, J Biol Chem 280(5):3963-73, 2005)from the brain stem and subjected to Western analysis using antibodiesdirected against TAU and several different phospho-isoforms thereof.

Quantitative analysis of the Western blots can reveal that in treatedanimals a robust and statistically significant reduction is detected forTAU phosphorylated at certain amino acids which are phospho-epitopes(for example serine 202, tyrosine 205 or tyrosine 231) and arepathologically relevant for disease since in Alzheimer's diseasepatients TAU is hyperphosphorylated at and hyperphosphorylation at thesesites has been implicated in aggregation and toxicity of TAU (Bertrandet al, Neuroscience 168(2):323-34, 2010; Luna-Muños et al, J AlzheimersDis. 12(4):365-75, 2007, Augustinack et al, Acta Neuropathol.103(1):26-35, 2002).

Example 77 In Vivo Inhibition of Tau-Instigated Pathologies

Human TAU R406W transgenic mice (J. of Neuroscience 24(19): 4657-4667,2004) are chronically treated between 2 weeks and 12 months with eitheran exemplary compound of this invention or vehicle only. The compoundtreated mice possess a longer average lifespan and display a delayedonset or progression of motor weakness compared to the vehicle controls.In addition compound treated mice have improved learning and memorycapabilities when performing the Morris water maze test.

At the end of the treatment period, mice are sacrificed and thecorresponding brains are used for biochemical and immunohistochemicalanalysis. The brains of compound treated mice are heavier than brains ofthe control group. In compound treated mice Western analysis shows thatTAU phosphorylation is reduced suggesting lowered formation ofpathological TAU species. Also a reduced accumulation of TAU is found inthe insoluble fraction of total brain extracts and/or the cerebral spinefluid (CSF) of compound treated mice. Immunohistochemical analysisshowed that compound treated mice have reduced accumulation offilamentous TAU aggregates in cerebral cortex, hippocampus, cerebellum,and spinal cord neurons.

Example 78 Construction of an α-Synuclein Over-Expressing Cell Line

An α-synuclein expression plasmid was constructed by sub-cloning theNcoI/XhoI fragment from 212T-SYN(WT) (Griffioen et al., Biochem BiophysActa (2006) 1762(3):312-318) containing the cDNA of human wild typeα-synuclein correspondingly into a standard mammalian expression vectorpcDNA3.1 resulting in plasmid pcDNA3.1-SYNwt. Plasmid pcDNA3.1 andpcDNA3.1-SYNwt were transfected to human neuroblastoma cells (ATCC No.CRL-2267) and independent clonal lines with the plasmids stablyintegrated into the genome were selected. These resulted in cell linesnamed M17 (transfected with pcDNA3.1) and M17-SYNwt (transfected withpcDNA3.1-SYNwt). Over-expression of α-synuclein in M17-SYNwt cell lineswas confirmed by Western analysis.

Example 79 Use of α-Synuclein Expressing Cells as a Model for NeuronalDegradation

Due to the high levels of α-synuclein M17-SYNwt cells are exquisitelysensitivity to paraquat, a well-known risk factor of synuclein-dependentneuronal degeneration. In degenerated or dead cells lactatedehydrogenase (LDH) is leaked out of the cells into the extracellularenvironment due to a loss of plasma-membrane integrity. This principleis used to determine cytotoxicity by quantifying the level of leaked LDHinto the growth medium.

The detailed method for determining α-synuclein cytotoxicity is asfollows: From appropriate precultures of M17 and M17-SYN cells areseeded at 50000 cells/cm² in Optimem Reduced Serum without phenol red(InVitrogen, Cat. 31985-047) supplemented with 5% fetal calf serum, 1 mMsodium pyruvate, 1×non-essential amino acids, 500 μg/ml G4180.5×antibiotic/antimycotic. After 3 h of incubation at 37° C./5% CO₂paraquat is added to the cells (final concentration of 32 mM), togetherwith the test compound and the cells are further incubated for 40 hours.Subsequently, LDH activity is determined using Promega Cytotox 96Non-Radioactive cytotoxicity assay, (Cat. G1780) according thesupplier's instructions.

FIG. 2 shows that treatment of M17-SYNwt cells, but not of M17 cellswith paraquat led to a relatively high level of LDH leaked into themedium demonstrating that α-synuclein mediates cellular degeneration orcell death in response to paraquat.

Example 80 Use of the α-Synuclein Expressing Cells in ScreeningCompounds

This α-synuclein expressing neuroblastoma cells make it possible toassess the ability of novel compounds to counteract α-synucleincytotoxicity. Active inhibitors of α-synuclein cytotoxicity are found toprovoke a decrease of LDH leakage in paraquat-treated M17-SYNwt cells.Since this method monitors leaked LDH from degenerated or dead cellsonly non-toxic compounds will be identified as active inhibitors ofα-synuclein-mediated cytotoxicity. Lack of toxicity is an importantcharacteristic for compounds to be used as a medicament to patients inneed. A compound is considered to be active in this test when itinhibits α-synuclein cytotoxicity by more than 25% relative to untreatedM17-SYNwt cells at a concentration of 20 μg/mL or lower. In theexperiments, the control group consists of M17-SYNwt cells treated withDMSO, the untreated paraquat group consists of M17-SYNwt cells treatedwith paraquat and DMSO, and the treated paraquat group consists ofM17-SYNwt cells to be treated with paraquat and the test compounddissolved in DMSO.

In order to determine EC₅₀ compounds are tested at differentconcentrations ranging from non-effective (thus at a relatively lowconcentration) to an effective (relatively high) concentration of testcompound. These data are also used for calculation of percent inhibition(% I). Percent inhibition is calculated as the synuclein toxicityinhibition by the compound in treated paraquat cells, relative to thesynuclein cytotoxicity in untreated paraquat cells. This corresponds tothe following equation:

(LDH release of treated paraquat cells at non-effective concentration oftest cmpd)−(LDH release of treated paraquat cells at most effectiveconcentration of test cmpd)/(LDH release of untreated paraquatcells)−(LDH release control cells)*100%

Example 81 Inhibition of Synuclein-Mediated Toxicity

The compounds are screened for activity using the α-synucleincytotoxicity assay as described above. Dose responses are carried out onall compounds found to be active (10 point curves in duplicate).

Example 82 In Vivo Inhibition of Synuclein-Mediated Instigated Loss ofSubstantia Nigra Neurons

In order to model neuronal loss in the substantia nigra region of thebrain, mice are treated with paraquat (intraperitoneal) at a dose nothigher than 8 mg/kg/day for a continuous period of 15-100 days. Thesemice are also chronically co-treated during that period with a compoundfrom table 1 administered at a dose (probably not higher than 20 mg/kgbody weight/day), or by vehicle only (no active compound). Micetreatment by means of vehicle or a compound of the invention start 2days before administration of paraquat.

At the end of the treatment period, mice are sacrificed and thecorresponding brains are used for immunohistochemical analysis. Thesubstantia nigra brain region has a relatively high percentage of cellswith high levels of tyrosine hydroxylase. Using antibodies raisedagainst tyrosin hydroxylase (anti-tyrosin hydroxylase), tyrosinehydroxylase containing neurons in the brains are detected. Quantitativeand comparative analysis of the tyrosin hydroxylase-positive stainedsubstantia nigra areas reveal a significantly larger TH-positive area inmice treated with compound versus vehicle treated mice.

Example 83 In Vivo Inhibition of 6-Hydroxydopamine (6-OHDA) InstigatedLoss of Substantia Nigra Neurons

Unilateral substantia nigra lesions are obtained by stereotacticstriatal injections of 6-hydroxydopamine in brains of living rats asdescribed by Vercammen et al. in Molecular Therapy, 14(5) 716-723(2006). These rats are also chronically co-treated with a compound oftable 1 or by vehicle only (no active compound). Daily treatment ofcompound or vehicle is started preferably 1 or 2 days beforeadministration of 6-OHDA and lasts between 7 to 30 days after the 6-OHDAinjection.

At the end of the treatment period, rats are sacrificed and thecorresponding brains are used for immunohistochemical analysis. Thesubstantia nigra brain region has a relatively high percentage of cellswith high levels of tyrosine hydroxylase. Using antibodies raisedagainst tyrosin hydroxylase (anti-tyrosine hydroxylase) tyrosinehydroxylase containing neurons in the brains are detected. The nigrallesion volumes and/or the tyrosine hydroxylase positive cell numbers arequantified as described in Vercammen et al. (cited supra). This analysisreveals that:

-   -   the nigral lesion volumes are significantly reduced in rats        treated with a compound according to this invention, as compared        to vehicle treated rats, thus indicating that the compound is        able to inhibit 6-OHDA triggered degeneration of substantia        nigra cells in vivo; and    -   tyrosine hydroxylase positive cell numbers are higher in rats        treated with a compound according to this invention as compared        to vehicle treated rats, thus providing confirmation that the        compound is able to inhibit 6-OHDA triggered degeneration of        substantia nigra cells in vivo.

Example 84 In Vitro Inhibition of α-Synuclein Aggregation

α-Synucleinopathies are characterised by aggregation of α-synuclein inneurons. Aggregation of purified α-synuclein is performed essentially asdescribed by Gerard et al. FASEB. 20(3):524-6 (2006). 20-100 μg purifiedα-synuclein (Sigma; S7820) at a concentration of about 2.5 μg/mL isincubated in the presence of spermin (250 μM) or paraquat (32 mM) or6-hydroxydopamine (400 μM) or vehicle in a 384 well plate. Spermin,paraquat and 6-hydroxydopamine promote the α-synuclein aggregationprocess. Aggregation kinetics is determined by measuring turbidity at340 nm, every 1-15 minutes for at least one hour. The same compounds, orvehicle only, is added to the different α-synuclein mixtures describedabove. This analysis reveals that, when a compound is present, themeasured turbidity is lower compared to reactions containing vehicleonly. This finding shows that the compound is able to inhibitaggregation of α-synuclein.

Exemplary compounds of the present invention are shown in table 2, withtheir chemical name and their EC₅₀ value (expressed in nM) as determinedfrom example 75 in the Tau-induced toxicity experiment.

TABLE 2 EC₅₀ CODE NAME (nM) Cpd002N-(2-(5-chloro-1H-indol-3-yl)ethyl)biphenyl-4- 130 carboxamide Cpd003N-(2-(5-fluoro-1H-indol-3-yl)ethyl)biphenyl-4- 448 carboxamide Cpd004N-(2-(5-methyl-1H-indol-3-yl)ethyl)biphenyl-4- 238 carboxamide Cpd005ethyl 5-amino-1-(4-(2-(5-methyl-1H-indol-3- 297yl)ethylcarbamoyl)phenyl)-1H-pyrazole-4-carboxylate Cpd006N-(2-(5-chloro-1H-indol-3-yl)ethyl)-2- 876 morpholinoisonicotinamideCpd007 N-(2-(5-fluoro-1H-indol-3-yl)ethyl)-2- 1078morpholinoisonicotinamide Cpd008N-(2-(5-chloro-1H-indol-3-yl)ethyl)biphenyl-2- 249 carboxamide Cpd010N-(2-(5-chloro-1H-indol-3-yl)ethyl)biphenyl-3- 187 carboxamide Cpd011N-(2-(5-chloro-1H-indol-3-yDethyl)-2′,6′- 236dimethylbiphenyl-4-carboxamide Cpd013N-(2-(5-chloro-1H-indol-3-yl)ethyl)-4′-hydroxybiphenyl- 77 3-carboxamideCpd014 N-(2-(5-chloro-1H-indol-3-yl)ethyl)-4′-hydroxybiphenyl- 574-carboxamide Cpd015N-(2-(5-chloro-1H-indol-3-yl)ethyl)-2′-methylbiphenyl- 381 2-carboxamideCpd019 N-(2-(5-chloro-1H-indol-3-yl)ethyl)-3′-methylbiphenyl- 7093-carboxamide Cpd021N-(2-(5-chloro-1H-indol-3-yl)ethyl)-4′-methylbiphenyl- 237 2-carboxamideCpd022 N-(2-(5-chloro-1H-indol-3-yl)ethyl)-4′-methylbiphenyl- 3543-carboxamide Cpd023N-(2-(5-chloro-1H-indol-3-yl)ethyl)-4′-methylbiphenyl- 235 4-carboxamideCpd024 N-(2-(5-chloro-1H-indol-3-yl)ethyl)-6- 765 morpholinonicotinamideCpd025 N-(2-(5-chloro-1H-indol-3-yl)ethyl)-2-(1H-pyrazol-1- 760yl)benzamide Cpd029 N-(2-(5-chloro-1H-indol-3-yl)ethyl)-3′- 523methoxybiphenyl-2-carboxamide Cpd032N-(2-(5-chloro-1H-indol-3-yl)ethyl)-4′- 200methoxybiphenyl-2-carboxamide Cpd033N-(2-(5-chloro-1H-indol-3-yl)ethyl)-4′- 223methoxybiphenyl-3-carboxamide Cpd034N-(2-(5-chloro-1H-indol-3-yl)ethyl)-4′- 91 methoxybiphenyl-4-carboxamideCpd035 N-(2-(5-chloro-1H-indol-3-yl)ethyl)-2′-fluorobiphenyl-2- 165carboxamide Cpd036N-(2-(5-chloro-1H-indol-3-yl)ethyl)-2′-fluorobiphenyl-3- 139 carboxamideCpd037 N-(2-(5-chloro-1H-indol-3-yl)ethyl)-2′-fluorobiphenyl-4- 61carboxamide Cpd038N-(2-(5-chloro-1H-indol-3-yl)ethyl)-3′-fluorobiphenyl-2- 226 carboxamideCpd039 N-(2-(5-chloro-1H-indol-3-yl)ethyl)-3′-fluorobiphenyl-4- 139carboxamide Cpd040N-(2-(5-chloro-1H-indol-3-yl)ethyl)-4′-fluorobiphenyl-2- 208 carboxamideCpd041 N-(2-(5-chloro-1H-indol-3-yl)ethyl)-4′-fluorobiphenyl-3- 186carboxamide Cpd042N-(2-(5-chloro-1H-indol-3-yl)ethyl)-4′-fluorobiphenyl-4- 228 carboxamideCpd043 N-(2-(5-chloro-1H-indol-3-yl)ethyl)-2′-cyanobiphenyl-3- 169carboxamide Cpd044N-(2-(5-chloro-1H-indol-3-yl)ethyl)-2′-cyanobiphenyl-4- 75 carboxamideCpd045 N-(2-(5-chloro-1H-indol-3-yl)ethyl)-3-(pyridin-4- 327yl)benzamide Cpd046 N-(2-(5-chloro-1H-indol-3-yl)ethyl)-4-(pyridin-4-269 yl)benzamide Cpd047N-(2-(5-chloro-1H-indol-3-yl)ethyl)-3′-fluorobiphenyl-3- 408 carboxamideCpd048 N-(2-(5-chloro-1H-indol-3-yl)ethyl)-3′-cyanobiphenyl-2- 232carboxamide Cpd049N-(2-(5-chloro-1H-indol-3-yl)ethyl)-3′-cyanobiphenyl-3- 61 carboxamideCpd050 N-(2-(5-chloro-1H-indol-3-yl)ethyl)-3′-cyanobiphenyl-4- 24carboxamide Cpd051N-(2-(5-chloro-1H-indol-3-yl)ethyl)-4′-cyanobiphenyl-2- 325 carboxamideCpd052 N-(2-(5-chloro-1H-indol-3-yl)ethyl)-4′-cyanobiphenyl-3- 112carboxamide Cpd053N-(2-(5-chloro-1H-indol-3-yl)ethyl)-4′-cyanobiphenyl-4- 85 carboxamideCpd054 2′-chloro-N-(2-(5-chloro-1H-indol-3-yl)ethyl)biphenyl-2- 170carboxamide Cpd0552′-chloro-N-(2-(5-chloro-1H-indol-3-yl)ethyl)biphenyl-3- 158 carboxamideCpd057 3′-chloro-N-(2-(5-chloro-1H-indol-3-yl)ethyl)biphenyl-2- 159carboxamide Cpd0583′-chloro-N-(2-(5-chloro-1H-indol-3-yl)ethyl)biphenyl-3- 186 carboxamideCpd059 3′-chloro-N-(2-(5-chloro-1H-indol-3-yl)ethyl)biphenyl-4- 130carboxamide Cpd0604′-chloro-N-(2-(5-chloro-1H-indol-3-yl)ethyl)biphenyl-3- 159 carboxamideCpd061 4′-chloro-N-(2-(5-chloro-1H-indol-3-yl)ethyl)biphenyl-4- 111carboxamide Cpd0634′-chloro-N-(2-(5-chloro-1H-indol-3-yl)ethyl)biphenyl-2- 154 carboxamideCpd064 N-(2-(5-chloro-1H-indol-3-yl)ethyl)-3′- 418(trifluoromethyl)biphenyl-2-carboxamide Cpd065N-(2-(5-chloro-1H-indol-3-yl)ethyl)-2′- 89(trifluoromethyl)biphenyl-3-carboxamide Cpd066N-(2-(5-chloro-1H-indol-3-yl)ethyl)-3′- 92(trifluoromethyl)biphenyl-4-carboxamide Cpd068N-(2-(5-chloro-1H-indol-3-yl)ethyl)-4′- 367(trifluoromethyl)biphenyl-3-carboxamide Cpd070N-(2-(5-chloro-1H-indol-3-yl)ethyl)-2′,6′- 606dimethylbiphenyl-3-carboxamide Cpd071N-(2-(5-chloro-1H-indol-3-yl)ethyl)-3′,4′- 546dimethylbiphenyl-2-carboxamide Cpd074N-(2-(5-chloro-1H-indol-3-yl)ethyl)-4′- 200(trifluoromethyl)biphenyl-4-carboxamide Cpd075N-(2-(5-chloro-1H-indol-3-yl)ethyl)-6-phenylpyridazine- 81 3-carboxamide

1. A compound of formula (A1) or a stereoisomer, enantiomer or tautomerthereof,

wherein, E is independently selected from CR³; and N; each R¹, R³, R⁴and R⁶ is independently selected from hydrogen; halogen; —OH; —OR¹⁰;—SH; —SR¹⁰; —S(O)R¹¹; —S(O)₂R¹¹; —SO₂NR¹²R¹³; trifluoromethyl;trifluoromethoxy; nitro; —NHC(O)R¹⁰; —NHS(O)₂R¹⁰; —NHC(O)NR¹²R¹³;—NR¹⁰C(O)R¹⁰; —NR¹⁰S(O)₂R¹⁰; —NR¹⁰C(O)NR¹²R¹³; —NR¹²R¹³; -cyano; —COOH;—COOR¹⁰; —C(O)NR¹²R¹³; —C(O)R¹¹; alkyl; alkenyl; alkynyl; aryl;heterocycle; arylalkylene; arylalkenylene; arylalkynylene;heterocycle-alkylene; heterocycle-alkenylene; andheterocycle-alkynylene; wherein the alkyl, alkenyl, alkynyl, aryl,heterocycle, arylalkylene, arylalkenylene, arylalkynylene,heterocycle-alkylene, heterocycle-alkenylene or heterocycle-alkynylene,includes no heteroatom or one or more heteroatoms in the alkyl(ene),alkenyl(ene) or alkynyl(ene) moiety, the heteroatoms being selected fromthe atoms O, S and N; wherein the alkyl, alkenyl, alkynyl, aryl,heterocycle, arylalkylene, arylalkenylene, arylalkynylene,heterocycle-alkylene, heterocycle-alkenylene or heterocycle-alkynyleneis unsubstituted or substituted with one or more Z; and wherein a carbonatom or heteroatom of the alkyl, alkenyl, alkynyl, aryl, heterocycle,arylalkylene, arylalkenylene, arylalkynylene, heterocycle-alkylene,heterocycle-alkenylene or heterocycle-alkynylene, is unoxidized oroxidized to form a C═O, C═S, N═O, N═S, S═O or S(O)₂; R² is selected fromhydrogen; alkyl; alkenyl; and alkynyl; R⁵ is independently selected fromhalogen; —OH; —OR¹⁰; —SH; —SR¹⁰; —S(O)R¹¹; —S(O)₂R¹¹; —SO₂NR¹²R¹³;trifluoromethyl; trifluoromethoxy; nitro; —NHC(O)R¹⁰; —NH S(O)₂R¹⁰;—NHC(O)NR¹²R¹³; —NR¹⁰C(O)R¹⁰; —NR¹⁰S(O)₂R¹⁰; —NR¹⁰C(O)NR¹²R¹³; —NR¹²R¹³;-cyano; —COOH; —COOR¹⁰; —C(O)NR¹²R¹³; —C(O)R¹¹; alkyl; alkenyl; alkynyl;aryl; heterocycle; arylalkylene; arylalkenylene; arylalkynylene;heterocycle-alkylene; heterocycle-alkenylene; andheterocycle-alkynylene; wherein the alkyl, alkenyl, alkynyl, aryl,heterocycle, arylalkylene, arylalkenylene, arylalkynylene,heterocycle-alkylene, heterocycle-alkenylene or heterocycle-alkynylene,includes no heteroatom or one or more heteroatoms in the alkyl(ene),alkenyl(ene) or alkynyl(ene) moiety, the heteroatoms being selected fromthe atoms O, S and N; wherein the alkyl, alkenyl, alkynyl, aryl,heterocycle, arylalkylene, arylalkenylene, arylalkynylene,heterocycle-alkylene, heterocycle-alkenylene or heterocycle-alkynyleneis unsubstituted or substituted with one or more Z; and wherein a carbonatom or heteroatom of the alkyl, alkenyl, alkynyl, aryl, heterocycle,arylalkylene, arylalkenylene, arylalkynylene, heterocycle-alkylene,heterocycle-alkenylene or heterocycle-alkynylene, is unoxidized oroxidized to form a C═O, C═S, N═O, N═S, S═O or S(O)₂; n is selected from0; 1; and 2; each of Y¹, Y², Y³, Y⁴ and Y⁵ is independently selectedfrom CZ¹; N; NR¹⁰¹; and CO; wherein at least two of Y¹, Y², Y³, Y⁴ andY⁵ are selected from CZ¹; B represents a cyclic structure selected fromcycloalkyl; cycloalkenyl; cycloalkynyl; aryl; and heterocycle; m isselected from 0; 1; 2; 3; 4 and 5; R⁸ is independently selected fromhydrogen; halogen; alkyl; alkenyl; alkynyl; —OH; —OR²⁰; —SH; —SR²⁰;—S(O)R²¹; —S(O)₂R²¹; —SO₂NR²²R²³; trifluoromethyl; trifluoromethoxy;nitro; —NHC(O)R²⁰; —NHS(O)₂R²⁰; —NHC(O)NR²²R²³; —NR²⁰C(O)R²⁰;—NR¹⁰S(O)₂R²⁰; —NR²⁰C(O)NR²²R²³; —NR²²R²³; -cyano; —COOH; —COOR²⁰;—C(O)NR²²R²³; and —C(O)R²¹; wherein the alkyl, alkenyl and alkynylincludes no heteroatom or one or more heteroatoms, the heteroatoms beingselected from the atoms O, S and N; wherein the alkyl, alkenyl andalkynyl is unsubstituted or substituted with one or more Z²; and whereina carbon atom or heteroatom of the alkyl, alkenyl and alkynyl, isunoxidized or oxidized to form a C═O, C═S, N═O, N═S, S═O or S(O)₂; eachZ is independently selected from halogen; —OH; —OR¹⁰; —SH; —SR¹⁰;—S(O)R¹¹; —S(O)₂R¹¹; —SO₂NR¹²R¹³; trifluoromethyl; trifluoromethoxy;nitro; —NHC(O)R¹⁰; —NHS(O)₂R¹⁰; —NHC(O)NR¹²R¹³; —NR¹⁰C(O)R¹⁰;—NR¹⁰S(O)₂R¹⁰; —NR¹⁰C(O)NR¹²R¹³; —NR¹²R¹³; -cyano; —COOH; —COOR¹⁰;—C(O)NR¹²R¹³; and —C(O)R¹¹; each Z¹ is independently selected fromhydrogen; alkyl; and Z²; each Z² is independently selected from halogen;—OH; —OR²⁰; —SH; —SR²⁰; —S(O)R²¹; —S(O)₂R²¹; —SO₂NR²²R²³;trifluoromethyl; trifluoromethoxy; nitro; —NHC(O)R²⁰; —NHS(O)₂R²⁰;—NHC(O)NR²²R²³; —NR²⁰C(O)R²⁰; —NR²⁰S(O)₂R²⁰; NR²⁰C(O)NR²²R²³; —NR²²R²³;-cyano; —COOH; —COOR²⁰; —C(O)NR²²R²³; and —C(O)R²¹; each R¹⁰ isindependently selected from alkyl; alkenyl; alkynyl; aryl; heterocycle;arylalkylene; arylalkenylene; arylalkynylene; heterocycle-alkylene;heterocycle-alkenylene and heterocycle-alkynylene; wherein the alkyl,alkenyl, alkynyl, aryl, heterocycle, arylalkylene, arylalkenylene,arylalkynylene, heterocycle-alkylene, heterocycle-alkenylene orheterocycle-alkynylene includes no heteroatom or one or more heteroatomsin the alkyl(ene), alkenyl(ene) or alkynyl(ene) moiety, the heteroatomselected from O, S and N; and wherein a carbon atom or heteroatom of thealkyl, alkenyl, alkynyl, aryl, heterocycle, arylalkylene,arylalkenylene, arylalkynylene, heterocycle-alkylene,heterocycle-alkenylene or heterocycle-alkynylene, is unoxidized oroxidized to form a C═O, C═S, N═O, N═S, S═O or S(O)₂; each R¹⁰¹ isindependently selected from hydrogen and R¹⁰; each R¹¹ is independentlyselected from hydroxyl; alkyl; alkenyl; alkynyl; aryl; heterocycle;arylalkylene; arylalkenylene; arylalkynylene; heterocycle-alkylene;heterocycle-alkenylene and heterocycle-alkynylene; and wherein thealkyl, alkenyl, alkynyl, aryl, heterocycle, arylalkylene,arylalkenylene, arylalkynylene, heterocycle-alkylene,heterocycle-alkenylene or heterocycle-alkynylene includes no heteroatomor one or more heteroatoms in the alkyl(ene), alkenyl(ene) oralkynyl(ene) moiety, the heteroatom selected from O, S and N; andwherein a carbon atom or heteroatom of the alkyl, alkenyl, alkynyl,aryl, heterocycle, arylalkylene, arylalkenylene, arylalkynylene,heterocycle-alkylene, heterocycle-alkenylene or heterocycle-alkynylene,is unoxidized or oxidized to form a C═O, C═S, N═O, N═S, S═O or S(O)₂;each R¹² and R¹³ is independently selected from hydrogen; alkyl;alkenyl; alkynyl; aryl; heterocycle; arylalkylene; arylalkenylene;arylalkynylene; heterocycle-alkylene; heterocycle-alkenylene andheterocycle-alkynylene; wherein the alkyl, alkenyl, alkynyl, aryl,heterocycle, arylalkylene, arylalkenylene, arylalkynylene, heterocycle-alkyl ene, heterocycle-alkenylene or heterocycle-alkynyleneincludes no heteroatom or one or more heteroatoms in the alkyl(ene),alkenyl(ene) or alkynyl(ene) moiety, the heteroatom selected from O, Sand N; and wherein a carbon atom or heteroatom of the alkyl, alkenyl,alkynyl, aryl, heterocycle, arylalkylene, arylalkenylene,arylalkynylene, heterocycle-alkylene, heterocycle-alkenylene orheterocycle-alkynylene, is unoxidized or oxidized to form a C═O, C═S,N═O, N═S, S═O or S(O)₂; and wherein R¹² and R¹³ can be taken together inorder to form a (4-, 5-, 6-, or 7-membered) heterocycle which isunsubstituted or substituted; each R²⁰ is independently selected fromalkyl; alkenyl; and alkynyl; wherein the alkyl, alkenyl, alkynylincludes no heteroatom or one or more heteroatoms in the alkyl, alkenylor alkynyl moiety, the heteroatom selected from O, S and N; and whereina carbon atom or heteroatom of the alkyl, alkenyl, alkynyl is unoxidizedor oxidized to form a C═O, C═S, N═O, N═S, S═O or S(O)₂; each R²¹ isindependently selected from hydroxyl; alkyl; alkenyl; and alkynyl;wherein the alkyl, alkenyl or alkynyl includes no heteroatom or one ormore heteroatoms in the alkyl, alkenyl or alkynyl moiety, the heteroatomselected from O, S and N; and wherein a carbon atom or heteroatom of thealkyl, alkenyl or alkynyl is unoxidized or oxidized to form a C═O, C═S,N═O, N═S, S═O or S(O)₂; each R²² and R²³ is independently selected fromhydrogen; alkyl; alkenyl; and alkynyl; wherein the alkyl, alkenyl oralkynyl includes no heteroatom or one or more heteroatoms in the alkyl,alkenyl or alkynyl moiety, the heteroatom selected from O, S and N;wherein a carbon atom or heteroatom of the alkyl, alkenyl or alkynyl isunoxidized or oxidized to form a C═O, C═S, N═O, N═S, S═O or S(O)₂; andwherein R²² and R²³ can be taken together in order to form a (4-, 5-,6-, or 7-membered) non-aromatic heterocycle which is unsubstituted orsubstituted; and solvates, hydrates, salts (pharmaceutically acceptablesalts, or prodrugs thereof.
 2. The compound of claim 1, havingstructural formula (A2) or (A3)

.
 3. The compound according to claim of claim 1, having structuralformula (B1), (B2) or (B3),

.
 4. The compound of claim 1, having structural formula (C1), (C2), or(C3),

.
 5. The compound of claim 1, wherein B is aryl and R⁸ is selected fromhydrogen, halogen, —OH, cyano, C₁₋₆alkyl, C₁₋₆alkoxy,C₁₋₆alkoxycarbonyl, trifluoromethyl; trifluoromethoxy.
 6. The compoundof claim 1, wherein each of R¹, R², R³, R⁴ and R⁶ are hydrogen.
 7. Thecompound of claim 1, having structural formula (I1), (I2), (I3), or (I4)

wherein R⁴ is selected from hydrogen and halogen; R⁵ is selected fromhalogen; —OH; —OR¹⁰; trifluoromethyl; trifluoromethoxy; cyano; —C(O)R¹¹;and C₁₋₆alkyl; n is selected from 0; 1; and 2; B represents a cyclicstructure selected from C₃₋₈cycloalkyl; C₆₋₁₀aryl; and heterocycle; m isselected from 0; 1; and 2; each R⁸ is independently selected fromhalogen; C₁₋₆alkyl; OH; C₁₋₆alkoxy; COOR²⁰; trifluoromethyl;trifluoromethoxy; and cyano; each R¹⁰ is C₁₋₆alkyl; each R¹¹ isC₁₋₆alkyl; each R²⁰ is C₁₋₆alkyl; wherein when B is ortho-phenyl informula (I1), then m is 1 or 2; and isomers, solvates, hydrates, orsalts thereof.
 8. The compound of claim 1, having structural formula(J1), (J2), (J3), or (J4)

wherein R⁴ is selected from hydrogen and halogen; R⁵ is selected fromhalogen; —OH; —OR¹⁰; trifluoromethyl; trifluoromethoxy; cyano; —C(O)R¹¹;and C₁₋₆alkyl; B represents a cyclic structure selected fromC₃₋₈cycloalkyl; C₆₋₁₀aryl; and heterocycle; m is selected from 0; 1; and2; each R⁸ is independently selected from halogen; C₁₋₆alkyl; OH;C₁₋₆alkoxy; COOR²⁰; trifluoromethyl; trifluoromethoxy; and cyano; eachR¹⁰ is C₁₋₆alkyl; each R¹¹ is C₁₋₆alkyl; each R²⁰ is C₁₋₆alkyl; whereinwhere B is ortho-phenyl in formula (J1), then m is 1 or 2; and isomers,solvates, hydrates, or salts thereof.
 9. A pharmaceutical compositioncomprising one or more pharmaceutically acceptable excipients and atherapeutically effective amount of the compound of claim
 1. 10.(canceled)
 11. A method of preventing or treating a neurodegenerativedisorder in a subject, the method comprising: administering to a subjectin need thereof a compound of claim 1 or a pharmaceutical composition ofclaim
 9. 12. The method according to claim 11, wherein theneurodegenerative disorder is selected from Alzheimer's disease, Pick'sdisease, corticobasal degeneration, progressive supranuclear palsy,frontotemporal dementia, parkinsonism, parkinsonism linked to chromosome17, FTDP-17, Parkinson's disease, diffuse Lewy body disease, traumaticbrain injury, amyotrophic lateral sclerosis, Niemann-Pick disease,Hallervorden-Spatz syndrome, Down syndrome, neuroaxonal dystrophy, andmultiple system atrophy.
 13. A compound of formula (VI) or astereoisomer, enantiomer or tautomer thereof,

each R¹, R³, R⁴ and R⁶ is independently selected from hydrogen; halogen;—OH; —OR¹⁰; —SH; —SR¹⁰; —S(O)R¹¹; —S(O)₂R¹¹; —SO₉NR¹²R¹³;trifluoromethyl; trifluoromethoxy; nitro; —NHC(O)R¹⁰; —NHS(O)₂R¹⁰;—NHC(O)NR¹²R¹³; —NR¹⁰C(O)R¹⁰; —NR¹⁰S(O)₂R¹⁰; —NR¹⁰C(O)NR¹²R¹³; —NR¹²R¹³;-cyano; —COOH; —COOR¹⁰; —C(O)NR¹²R¹³; —C(O)R¹¹; alkyl; alkenyl; alkynyl;aryl; heterocycle; arylalkylene; arylalkenylene; arylalkynylene;heterocycle-alkylene; heterocycle-alkenylene; andheterocycle-alkynylene; wherein the alkyl, alkenyl, alkynyl, aryl,heterocycle, arylalkylene, arylalkenylene, arylalkynylene,heterocycle-alkylene, heterocycle-alkenylene or heterocycle-alkynylene,includes no heteroatom or one or more heteroatoms in the alkyl(ene),alkenyl(ene) or alkynyl(ene) moiety, the heteroatoms being selected fromthe atoms O, S and N; wherein the alkyl, alkenyl, alkynyl, aryl,heterocycle, arylalkylene, arylalkenylene, arylalkynylene,heterocycle-alkylene, heterocycle-alkenylene or heterocycle-alkynyleneis unsubstituted or substituted with one or more Z; and wherein a carbonatom or heteroatom of the alkyl, alkenyl, alkynyl, aryl, heterocycle,arylalkylene, arylalkenylene, arylalkynylene, heterocycle-alkylene,heterocycle-alkenylene or heterocycle-alkynylene, is unoxidized oroxidized to form a C═O, C═S, N═O, N═S, S═O or S(O)₂; R² is selected fromhydrogen; alkyl; alkenyl; and alkynyl; R⁵ is independently selected fromhalogen; —OH; —OR¹⁰; —SH; —SR¹⁰; —S(O)R¹¹; —S(O)₂R¹¹; —SO₂NR¹²R¹³;trifluoromethyl; trifluoromethoxy; nitro; —NHC(O)R¹⁰; —NHS(O)₂R¹⁰;—NHC(O)NR¹²R¹³; —NR¹⁰C(O)R¹⁰; —NR¹⁰S(O)₂R¹⁰; —NR¹⁰C(O)NR¹²R¹³; —NR¹²R¹³;-cyano; —COOH; —COOR¹⁰; —C(O)NR¹²R¹³; —C(O)R¹¹; alkyl; alkenyl; alkynyl;aryl; heterocycle; arylalkylene; arylalkenylene; arylalkynylene;heterocycle-alkylene; heterocycle-alkenylene; andheterocycle-alkynylene; wherein the alkyl, alkenyl, alkynyl, aryl,heterocycle, arylalkylene, arylalkenylene, arylalkynylene,heterocycle-alkylene, heterocycle-alkenylene or heterocycle-alkynylene,includes no heteroatom or one or more heteroatoms in the alkyl(ene),alkenyl(ene) or alkynyl(ene) moiety, the heteroatoms being selected fromthe atoms O, S and N; wherein the alkyl, alkenyl, alkynyl, aryl,heterocycle, arylalkylene, arylalkenylene, arylalkynylene,heterocycle-alkylene, heterocycle-alkenylene or heterocycle-alkynyleneis unsubstituted or substituted with one or more Z; and wherein a carbonatom or heteroatom of the alkyl, alkenyl, alkynyl, aryl, heterocycle,arylalkylene, arylalkenylene, arylalkynylene, heterocycle-alkylene,heterocycle-alkenylene or heterocycle-alkynylene, is unoxidized oroxidized to form a C═O, C═S, N═O, N═S, S═O or S(O)₂; n is selected from0; 1; and 2; each of Y¹, Y², Y³, Y⁴ and Y⁵ is independently selectedfrom CZ¹; N; NR¹⁰¹; and CO; wherein at least two of Y¹, Y², Y³, Y⁴ andY⁵ are selected from CZ¹; R⁸ is independently selected from hydrogen;halogen; alkyl; alkenyl; alkynyl; —OH; —OR²⁰; —SH; —SR²⁰; —S(O)R²¹;—SO₂NR²²R²³; trifluoromethyl; trifluoromethoxy; nitro; —NHC(O)R²⁰;—NHS(O)₂R²⁰; —NHC(O)NR²²R²³; —NR²⁰C(O)R²⁰; —NR¹⁰S(O)₂R²⁰;—NR²⁰C(O)NR²²R²³; —NR²²R²³; -cyano; —COOH; —COOR²⁰; —C(O)NR²²R²³; and—C(O)R²¹; wherein the alkyl, alkenyl and alkynyl includes no heteroatomor one or more heteroatoms, the heteroatoms being selected from theatoms O, S and N; wherein the alkyl, alkenyl and alkynyl isunsubstituted or substituted with one or more Z²; and wherein a carbonatom or heteroatom of the alkyl, alkenyl and alkynyl, is unoxidized oroxidized to faun a C═O, C═S, N═O, N═S, S═O or S(O)₂; each Z isindependently selected from halogen; —OH; —OR¹⁰; —SH; —SR¹⁰; —S(O)R¹¹;—S(O)₂R¹¹; —SO₂NR¹²R¹³; trifluoromethyl; trifluoromethoxy; nitro;—NHC(O)R¹⁰; —NHS(O)₂R¹⁰; —NHC(O)NR¹²R¹³; —NR¹⁰C(O)R¹⁰; —NR¹⁰S(O)₂R¹⁰;—NR¹⁰C(O)NR¹²R¹³; —NR¹²R¹³; -cyano; —COOH; —COOR¹⁰; —C(O)NR¹²R¹³; and—C(O)R¹¹; each Z¹ is independently selected from hydrogen; alkyl; andZ²; each Z² is independently selected from halogen; —OH; —OR²⁰; —SH;—SR²⁰; —S(O)R²¹; —S(O)₂R²¹; —SO₂NR²²R²³; trifluoromethyl;trifluoromethoxy; nitro; —NHC(O)R²⁰; —NHS(O)₂R²⁰; —NHC(O)NR²²R²³;—NR²⁰C(O)R²⁰; —NR²⁰S(O)₂R²⁰; —NR²⁰C(O)NR²²R²³; —NR²²R²³; -cyano; —COOH;—COOR²⁰; —C(O)NR²²R²³; and —C(O)R²¹; each R¹⁰ is independently selectedfrom alkyl; alkenyl; alkynyl; aryl; heterocycle; arylalkylene;arylalkenylene; arylalkynylene; heterocycle-alkylene;heterocycle-alkenylene and heterocycle-alkynylene; wherein the alkyl,alkenyl, alkynyl, aryl, heterocycle, arylalkylene, arylalkenylene,arylalkynylene, heterocycle-alkylene, heterocycle-alkenylene orheterocycle-alkynylene includes no heteroatom or one or more heteroatomsin the alkyl(ene), alkenyl(ene) or alkynyl(ene) moiety, the heteroatomselected from O, S and N; and wherein a carbon atom or heteroatom of thealkyl, alkenyl, alkynyl, aryl, heterocycle, arylalkylene,arylalkenylene, arylalkynylene, heterocycle-alkylene,heterocycle-alkenylene or heterocycle-alkynylene, is unoxidized oroxidized to form a C═O, C═S, N═O, N═S, S═O or S(O)₂; each R¹⁰¹ isindependently selected from hydrogen and R¹⁰; each R¹¹ is independentlyselected from hydroxyl; alkyl; alkenyl; alkynyl; aryl; heterocycle;arylalkylene; arylalkenylene; arylalkynylene; heterocycle-alkylene;heterocycle-alkenylene and heterocycle-alkynylene; wherein the alkyl,alkenyl, alkynyl, aryl, heterocycle, arylalkylene, arylalkenylene,arylalkynylene, heterocycle-alkylene, heterocycle-alkenylene orheterocycle-alkynylene includes no heteroatom or one or more heteroatomsin the alkyl(ene), alkenyl(ene) or alkynyl(ene) moiety, the heteroatomselected from O, S and N; and wherein a carbon atom or heteroatom of thealkyl, alkenyl, alkynyl, aryl, heterocycle, arylalkylene,arylalkenylene, arylalkynylene, heterocycle-alkylene,heterocycle-alkenylene or heterocycle-alkynylene, is unoxidized oroxidized to form a C═O, C═S, N═O, N═S, S═O or S(O)₂; each R¹² and R¹³ isindependently selected from hydrogen; alkyl; alkenyl; alkynyl; aryl;heterocycle; arylalkylene; arylalkenylene; arylalkynylene;heterocycle-alkylene; heterocycle-alkenylene and heterocycle-alkynylene;wherein the alkyl, alkenyl, alkynyl, aryl, heterocycle, arylalkylene,arylalkenylene, arylalkynylene, heterocycle-alkylene,heterocycle-alkenylene or heterocycle-alkynylene includes no heteroatomor one or more heteroatoms in the alkyl(ene), alkenylene) oralkynyl(ene) moiety, the heteroatom selected from O, S and N; wherein acarbon atom or heteroatom of the alkyl, alkenyl, alkynyl, aryl,heterocycle, arylalkylene, arylalkenylene, arylalkynylene,heterocycle-alkylene, heterocycle-alkenylene or heterocycle-alkynylene,is unoxidized or oxidized to form a C═O, C═S, N═O, N═S, S═O or S(O)₂;and wherein R¹² and R¹³ can be taken together in order to form a (4-,5-, 6-, or 7-membered) heterocycle which is unsubstituted orsubstituted; each R²⁰ is independently selected from alkyl; alkenyl; andalkynyl; wherein the alkyl, alkenyl, alkynyl includes no heteroatom orone or more heteroatoms in the alkyl, alkenyl or alkynyl moiety, theheteroatom selected from O, S and N; and wherein a carbon atom orheteroatom of the alkyl, alkenyl, alkynyl is unoxidized or oxidized toform a C═O, C═S, N═O, N═S, S═O or S(O)₂; each R²¹ is independentlyselected from hydroxyl; alkyl; alkenyl; and alkynyl; wherein the alkyl,alkenyl or alkynyl includes no heteroatom or one or more heteroatoms inthe alkyl, alkenyl or alkynyl moiety, the heteroatom selected from O, Sand N; and wherein a carbon atom or heteroatom of the alkyl, alkenyl oralkynyl is unoxidized or oxidized to form a C═O, C═S, N═O, N═S, S═O orS(O)₂; each R²² and R²³ is independently selected from hydrogen; alkyl;alkenyl; and alkynyl; wherein the alkyl, alkenyl or alkynyl includes noheteroatom or one or more heteroatoms in the alkyl, alkenyl or alkynylmoiety, the heteroatom selected from O, S and N; wherein a carbon atomor heteroatom of the alkyl, alkenyl or alkynyl is unoxidized or oxidizedto form a C═O, C═S, N═O, N═S, S═O or S(O)₂; and wherein R²² and R²³ canbe taken together in order to form a (4-, 5-, 6-, or 7-membered)non-aromatic heterocycle which is unsubstituted or substituted; and LGis a leaving group; or a solvate, hydrate, salt or prodrug thereof. 14.A method for the preparation of the compounds of claim 1, and isomers,solvates, hydrates, salts, or prodrugs thereof, the method comprising:reacting a substituted or unsubstituted (1H-indol-3-yl)methanamine,2-(1H-indol-3-yl)ethanamine or 3-(1H-indol-3-yl)propan-1-amine with acorrectly substituted six membered ring derivative bearing an acidhalide function in a polar aprotic solvent in the presence of a strongbase at a temperature between −10° C. to 100° C.; reacting a substitutedor unsubstituted (1H-indol-3-yl)methanamine, 2-(1H-indol-3-yl)ethanamineor 3-(1H-indol-3-yl)propan-1-amine with a correctly substituted sixmembered ring derivative bearing one carboxylic acid function in a polaraprotic solvent in the presence of a peptide bond formation couplingagent at a temperature between 0° C. to 50° C.
 15. (canceled) 16.(canceled)
 17. The method according to claim 14, further comprising:wherein the six membered ring bears a leaving group (LG), reacting thecompound with suitable nucleophiles and in the presence of a strong baseor reacting the compound with derivatives in the presence of a palladiumor copper catalyst.
 18. The method according to claim 17, wherein thesuitable nucleophiles are amines or alcohols.
 19. The method accordingto claim 17, wherein the derivatives are selected from boronic acids,stannane, and organozinc derivatives.